perampanel and Epilepsy

In the present meta-analysis, the efficacy and safety of perampanel (PER) for the treatment of adolescents with epilepsy were assessed.. Keyword searches were performed in Embase, PubMed, Cochrane Library, Web of Science, EBSCO and CNKI from 1 January 2020 to 10 October 2020. The randomized controlled trials (RCTs) and case-control studies in which PER was compared with other Anti-seizure drugs (ASDs) and/or placebo in children with epilepsy, were considered eligible studies. Odds ratio (OR) with 95% confidence interval (95% CI) for the dichotomous outcome statistic was calculated using a fixed-effects or random-effects model.. Three RCTs with a total of 372 adolescents' patients were included in this meta-analysis. Placebo was used as a control in these studies. Compared with placebo, PER showed better efficacy in median seizure frequency reduction from baseline per 28 days (OR = 2.49, 95% CI: 1.25-4.96,. Based on the results in this study, PER showed better efficacy than placebo therapy in children with epilepsy and the AEs were similar in PER group and placebo group. PER showed good efficacy and a low risk of AEs, and might be a promising medication for the treatment of pediatric epilepsy. In the future, well-designed and large-scale RCTs are necessary to validate the present findings.

Topics: Adolescent; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Humans; Treatment Outcome

To investigate the safety of perampanel in different disorders and doses.. Embase, the Cochrane Library, Medline, and ClinicalTrials.gov were searched from inception to July 2022 for randomized controlled trials (RCTs). The meta-analysis was performed by using Review Manager 5.3 and R 4.2.1 software.. A total of 17 RCTs with 5711 subjects were included in the final analysis. The double-blind treatment phase was from 12 weeks to 48 weeks. Our results showed that 11 adverse events (aggression, ataxia, balance disorder, dizziness, fall, fatigue, irritability, rash, somnolence, vertigo, and weight increase) were statistically significantly associated with perampanel, and 4 of them (ataxia, dizziness, fatigue, and somnolence) showed a clear dose-response relationship. Psychiatric adverse events occurred most frequently among serious treatment-emergent adverse events (TEAEs). At 8 mg/day, seven adverse events (aggression, balance disorder, dizziness, fatigue, irritability, vertigo, and weight increase) occurred more frequently in patients with epilepsy than in patients with other disorders, whereas dose discontinuation rates due to adverse events were lower in patients with epilepsy than in patients with other disorders.. The safety profile of perampanel is dependent on diseases and dose. The risk of adverse events was statistically significantly higher, with doses exceeding 4 mg/day. Despite a higher risk of adverse events, patients with epilepsy had a lower perampanel discontinuation rate than patients with other disorders.

Topics: Anticonvulsants; Ataxia; Dizziness; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Fatigue; Humans; Pyridones; Randomized Controlled Trials as Topic; Sleepiness; Treatment Outcome; Vertigo

Perampanel (PER) is a novel antiepileptic drug. The efficacy, tolerability and safety of PER in children and adolescents with epilepsy are still unclear. We aimed to study the efficacy and safety of PER in children and adolescents with epilepsy.. We searched PubMed, Embase and Cochrane Library for relevant literature up to November 2022. Then we extracted the relevant data from eligible literature for systematic review and meta-analysis.. Twenty-one studies involving 1968 children and adolescent patients were included. A reduction in seizure frequency of at least 50 percent occurred in 51.5% (95% confidence interval [CI] [47.1%, 55.9%]) of patients. Complete seizure cessation occurred in 20.6% (95%CI [16.7%, 25.4%]). The incidence of adverse events was 40.8% (95%CI [33.8%, 48.2%]). The most common adverse events were drowsiness 15.3% (95% CI [13.7%, 16.9%]), irritability 9.3% (95%CI [8.0%, 10.6%]), dizziness 8.4% (95% CI [7.2%, 9.7%]). The incidence of drug discontinuation due to adverse events was 9.2% (95% CI [7.0%, 11.5%]).. PER is generally well tolerated and effective in the treatment of epilepsy in children and adolescents. Larger studies are still needed to explore the application of PER in children and adolescents.. The funnel plot suggests that there may be publication bias in our meta-analysis, and most of the included studies were Asian, so there may be some racial differences.

Topics: Adolescent; Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Humans; Seizures; Treatment Outcome

The aim of the study was to summarize the findings of the studies documenting the efficacy and safety of perampanel when used in children/adolescents or adults, either as add-on therapy or as monotherapy.. A systematic search was conducted using PubMed, EMBASE and Scopus. Only studies with a cohort-based approach (either prospective or retrospective) were included. We were interested in real-world studies and therefore, studies with a highly regulated environment, such as randomized controlled trials, were excluded. The primary outcomes of interest were retention rates, response rates and seizure-free rates. Random effects model was used for the analysis. Effect sizes were reported as pooled prevalence along with 95% confidence intervals.. A total of 34 studies were included. The retention rates, within 24 months from initiation of treatment as an add-on therapy, ranged between 65% to 77% among children and adolescents. For adults, the retention rate varied between 56 to 77% within 24 months from initiation of treatment. The response rate was around 70% in children/adolescents and 52% in adults at 24 months of follow-up. Around 25% of children and adolescents and 37% of adults were seizure-free at 24 months follow-up period. The proportion of children/adolescents and adults reporting any treatment-related adverse effects was 29% and 41%, respectively. The commonly reported adverse effects were dizziness/drowsiness, somnolence, behavioral problems (irritability, aggression, anxiety, mood changes), postural instability/gait problems, fatigue and weight gain.. Perampanel might be an effective anti-epileptic drug in both children/adolescents and adults when used as an adjunct therapy. More data is required to comment on its use as monotherapy. Careful monitoring for psychiatric problems and behavioral disturbances is required, both prior to initiating treatment as well as during the course of management. Studies with long-term follow-up may are needed to confirm the findings of this meta-analysis.

Topics: Adolescent; Adult; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Humans; Nitriles; Prospective Studies; Retrospective Studies; Treatment Outcome

This study reported the first case of Kohlschütter-Tönz syndrome (KTS) in China and reviewed the literature of the reported cases.. This patient was registered at the Children's Hospital of Chongqing Medical University. The patient's symptoms and treatments were recorded in detail, and the patient was monitored for six years. We employed a combination of the following search terms and Boolean operators in our search strategy: Kohlschütter-Tönz syndrome, KTS, and ROGDI. These terms were carefully selected to capture a broad range of relevant publications in PubMed, Web of Science, WHO Global Health Library, and China National Knowledge Infrastructure, including synonyms, variations, and specific terms related to KTS. The pathogenicity of the variants was predicted using SpliceAI and MutationTaster, and the structures of the ROGDI mutations were constructed using I-TASSER.. This is the first case report of KTS in China. Our patient presented with epilepsy, global developmental delay, and amelogenesis imperfecta. A trio-WES revealed homozygous mutations in ROGDI (c.46-37_46-30del). The brain magnetic resonance imaging (MRI) and video electroencephalogram (VEEG) were normal. The efficacy of perampanel (PMP) in treating seizures and intellectual disability was apparent. Furthermore, 43 cases of ROGDI-related KTS were retrieved. 100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta. 17.2% received a diagnosis of attention deficit hyperactivity disorder (ADHD), and 3.4% were under suspicion of autism spectrum disorder (ASD). Language disorders were observed in all patients. Emotional disorders, notably self-harm behaviors (9.1%), were also reported.. ROGDI-related KTS is a rare neurodegenerative disorder, characterized by three classic clinical manifestations: epilepsy, global developmental delay, and amelogenesis imperfecta. Moreover, patients could present comorbidities, including ADHD, ASD, emotional disorders, and language disorders. PMP may be a potential drug with relatively good efficacy, but long-term clinical trials are still needed.

Topics: Amelogenesis Imperfecta; Autism Spectrum Disorder; Child; Epilepsy; Humans; Language Disorders; Membrane Proteins; Nuclear Proteins

This systematic review was conducted to reveal the cognitive effects of perampanel (PER) as assessed by objective standardized neuropsychological measures in patients with epilepsy. A systematic literature search was performed in PubMed. In addition we cross-checked a list of relevant studies (based on a ProQuest search) provided by Eisai GmbH. Eligibility criteria were (1) group studies reporting the cognitive outcome of treatment with PER in patients with epilepsy (2) which employed objective cognitive tests and (3) were published in English. Of the 56 initially retrieved records, 9 eligible studies were included in the qualitative synthesis. Two studies were based on the very same sample. Altogether the included studies analyzed a total of 241 patients (46% pediatric) with adjunctive PER. All studies were longitudinal with assessments before and after introduction of PER (up to 5 follow-ups and observation intervals of up to 1 year). Two studies were retrospective, 6 lacked a control condition. Neuropsychological assessments varied in extent and test selection. Overall no systematic cognitive deteriorations or improvements after introduction of PER have been reported across the analyzed studies. The only randomized placebo-controlled trial found a transient worsening in attention and speed of memory at the 19-week follow-up, and in addition a late decline in another parameter of attention at the final 52-week follow-up. This systematic review on the objective cognitive effects of PER suggests an overall neutral cognitive profile of PER with no systematic cognitive deteriorations or improvements. More controlled studies on the cognitive effects of PER would be appreciated.

Topics: Anticonvulsants; Child; Cognition; Epilepsy; Humans; Neuropsychological Tests; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Retrospective Studies

The last decade has seen an increase in the use of anti-seizure medications (ASMs); however, the burden of treating drug-resistant epilepsy has not fallen. We performed this meta-analysis to evaluate the optimal dose of Perampanel (PER) as a new adjunctive treatment for drug-resistant seizures.. We searched for studies published from inception to February 1, 2021 from PubMed, Central Register of Controlled Trials (CENTRAL), and ScienceDirect. Research characteristics, patients' characteristics, and treatment regimen, concomitant ASMs, clinical outcomes were extracted. The practical outcome included a reduction in seizures frequency ≥50%, ≥75%, and ≥100% from baseline convulsive seizure frequency, and the safety outcome included the proportion of drug withdrawal and adverse reactions. Odds ratios (OR) for 95% confidence intervals (95% CI) were estimated by the inverse variance method.. Four trials which enrolled 2187 participants (1569 in the PER group and 618 in the placebo group) were included. Results showed that 8 or 12 mg per day had the best effect on all three outcomes, with no significant difference between 8 and 12 mg per day (≥50% reduction, 35.5% vs 36.1%, P = .84; ≥75% reduction, 17.8% vs 19.1%, P = .64; seizure-free, 3.5% vs 3.7%, P = .85). In addition, 12-mg PER compared to 8 mg had a higher proportion of trial withdrawal (8.7% vs 17.0%; P < .00001) and treatment-emergent adverse event (TEAE) resulting in dose reduction/discontinuation (18.5% vs 32.0%; P < .00001). The adverse events (AEs) significantly associated with adjunctive PER were dizziness, somnolence, fatigue, and irritability.. Adjunctive treatment of PER was associated with a more significant reduction in the frequency of seizures in patients with refractory epilepsy than placebo, but with a higher frequency of AEs. PER at a daily dose of 8 mg appears to have the best ratio between efficacy and tolerance in most study participants.

Topics: Anticonvulsants; Drug Resistant Epilepsy; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Perampanel (PER) has been used clinically as monotherapy and adjunctive therapy for focal seizures and as adjunctive therapy for generalized tonic-clonic seizures in epilepsy patients in Japan. In recent years in Japan and worldwide, clinical studies have been conducted on patients with various seizure types of epilepsy. The results have shown that PER has broad spectrum properties. The pooled analysis of controlled trials (PERMIT study) showed PER efficacy in patients with status epilepticus, myoclonic seizures, and absence seizures. In addition, PER has been shown to be safe and effective in patients with juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, and elderly-onset epilepsy that are often difficult to treat with narrow-spectrum ASM. In this review article, we summarize the latest findings on PER, and overview the broad spectrum characteristics of PER. In addition, we discuss the optimal use of PER for patients with epilepsy, focusing on low-dose initiation and on slow titration of PER to minimize adverse events. (Received December 7, 2021; Accepted March 29, 2022; Published July 1, 2022).

Topics: Aged; Anticonvulsants; Epilepsy; Epilepsy, Generalized; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Prospective Studies; Pyridones; Retrospective Studies; Treatment Outcome

Perampanel a third-generation antiseizure medication, belongs to a new promising class of drugs called AMPA receptor antagonists, approved to treat focal-onset seizures with or without focal to bilateral tonic clonic seizures and primary generalized tonic-clonic seizures.. This review included RCTs on patients with epilepsy exposed to perampanel compared with placebo, or one or more pre-existing antiseizure medications. Four databases and two clinical trial registries were searched from inception to July 2021. Included outcomes were 50% responder rate, seizure-free rate, discontinuation due to treatment-emergent adverse events (TEAE)s, having any TEAEs, and most reported TEAEs. Cochrane risk of bias tool was used to assess the internal validity of the included RCTs.. From 2211 retrieved citations, eight RCTs were included in the meta-analysis. Fifty-percent responder and seizure freedom rates were significantly higher in patients receiving perampanel when compared to placebo (RR 1.57, 95 % CI 1.35 to 1.82, I. This systematic review reports significant reduction in seizures and a potential dose-based increase in discontinuations due to TEAE. The most-reported TEAEs were non-threatening, with the possibility of rare but serious adverse psychological outcomes. Further independent RCTs studying the most efficient dose for efficacy and safety are needed.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

There is a need for anti-seizure medications (ASMs) that are well tolerated and effective as monotherapy or first adjunctive therapy to reduce the need for adjunctive ASMs to treat newly diagnosed epilepsy, and to reduce the number of concomitant ASMs in patients with refractory epilepsy. Although the pivotal trials of perampanel evaluated its adjunctive use in patients with refractory seizures, open-label/real-world studies support its use in first/second-line settings.. This paper reviews the pharmacology, efficacy, and safety/tolerability of perampanel, focusing on its use as monotherapy or first adjunctive therapy. The safety of perampanel in special populations and its safety/tolerability compared with that of other ASMs is also discussed.. Perampanel is a favorable candidate for initial or first adjunctive therapy due to its favorable efficacy and safety/tolerability as monotherapy and adjunctive therapy, its long half-life and ease of use, and its limited drug-drug interactions. The proposed mitigation strategies for managing the risk of serious psychiatric adverse events are appropriate patient selection, use of low doses, and slow titration. The growing body of evidence might shift current treatment strategies toward the early use of perampanel and its use at a low dose (4 mg/day).

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Treatment Outcome

Perampanel (PER) is an antiepileptic drug approved in Europe as add-on therapy for patients with focal onset seizures (with or without secondary generalisation) from the age of 4 years, and for primary generalised tonic-clonic seizures from 7 years of age.. Review current evidence on treatment with PER monotherapy after conversion from adjunctive therapy.. Two retrospective multicentre studies in which PER was used as monotherapy show that low doses (6-8 mg/day) of PER were effective and well tolerated in a subgroup of patients with less severe epilepsies than patients who participated in clinical trials (where PER was used as add-on therapy). In these studies, the retention rate exceeded 90% at 3 months, and 70% at 6, and 12 months. The responder rate was > 75% at 3 months, and the rate of seizure-free patients exceeded 50% at 3 and 6 months, and 37% at 12 months. Compared to other observational studies and clinical trials where PER was used as add-on therapy, no adverse effects other than those already known were observed. Four other studies examining the effects of conversion to PER monotherapy in a small number of patients support these results.. In routine clinical practice, conversion to PER monotherapy, at relatively low doses, is an effective and well-tolerated treatment for patients with focal and generalised tonic-clonic seizures.. Tratamiento de la epilepsia con perampanel: desde la terapia añadida a la conversión a monoterapia.. Introducción.El perampanel (PER) es un fármaco anticrisis epilépticas aprobado en Europa como terapia añadida para pacientes con crisis de inicio focal (con o sin crisis focal a bilateral tonicoclónica) desde los 4 años, y para las crisis tonicoclónicas generalizadas desde los 7 años. Objetivo. Revisar la evidencia existente sobre el tratamiento con PER en conversión a monoterapia. Desarrollo. Dos estudios multicéntricos retrospectivos en los que el PER se convirtió a monoterapia muestran que este fármaco en dosis bajas (6-8 mg/día) fue especialmente eficaz y bien tolerado en un subgrupo de pacientes con epilepsias menos graves que los pacientes que participaron en los ensayos clínicos en donde el PER se empleó como terapia añadida. En estos estudios, la tasa de retención superó el 90% a los tres meses y el 70% a los seis y a los 12 meses. La tasa de respondedores fue > 75% a los tres meses, y la tasa de pacientes libres de crisis llegó a superar el 50% a los tres y a los seis meses, y el 37% a los 12 meses. En comparación con otros estudios donde el PER se empleó como terapia añadida, no se observaron efectos adversos diferentes a los ya conocidos. Otros cuatro estudios que examinaron los efectos del PER en conversión a monoterapia en un número pequeño de pacientes apoyan estos resultados. Conclusiones. En la práctica clínica habitual, el PER es un tratamiento eficaz y bien tolerado cuando se usa en conversión a monoterapia, en dosis relativamente bajas, en pacientes con crisis focales y tonicoclónicas generalizadas.

Topics: Child; Child, Preschool; Epilepsy; Humans; Nitriles; Pyridones; Treatment Outcome

Perampanel (PER) is a novel antiepileptic drug (AED) which employs a completely different mechanism of action compared to existing medications. Overall, PER is considered to be safe up to a dose of 12 mg per day. When used to treat refractory and super-refractory status epilepticus, PER seems to be extremely well tolerated; this is true even when used at doses of up to 32 mg. There are currently only three case reports on the effects of acute PER overdose in epilepsy patients.. We report a 16-year-old Thai woman with a low body weight, who took PER at a dose of 40 times that of the prescribed daily dose. She experienced only an alteration of consciousness, without any systemic medical effects, and made a full recovery within 3 days without gastric lavage or specific treatment.. Our report demonstrates that an acute PER overdose may not produce serious adverse systemic effects. Individuals with adverse central nervous system (CNS) effects, such as altered consciousness, can experience a rapid recovery.

Topics: Adolescent; Anticonvulsants; Body Mass Index; Epilepsy; Female; Humans; Nitriles; Pyridones; Treatment Outcome

Glutamate is considered as the predominant excitatory neurotransmitter in the mammalian central nervous systems (CNS). Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the main glutamate-gated ionotropic channels that mediate the majority of fast synaptic excitation in the brain. AMPARs are highly dynamic that constitutively move into and out of the postsynaptic membrane. Changes in the postsynaptic number of AMPARs play a key role in controlling synaptic plasticity and also brain functions such as memory formation and forgetting development. Impairments in the regulation of AMPAR function, trafficking, and signaling pathway may also contribute to neuronal hyperexcitability and epileptogenesis process, which offers AMPAR as a potential target for epilepsy therapy. Over the last decade, various types of AMPAR antagonists such as perampanel and talampanel have been developed to treat epilepsy, but they usually show limited efficacy at low doses and produce unwanted cognitive and motor side effects when administered at higher doses. In the present article, the latest findings in the field of molecular mechanisms controlling AMPAR biology, as well as the role of these mechanism dysfunctions in generating epilepsy will be reviewed. Also, a comprehensive summary of recent findings from clinical trials with perampanel, in treating epilepsy, glioma-associated epilepsy and Parkinson's disease is provided. Finally, antisense oligonucleotide therapy as an alternative strategy for the efficient treatment of epilepsy is discussed.

Topics: Animals; Anticonvulsants; Epilepsy; Humans; Neuronal Plasticity; Nitriles; Oligonucleotides, Antisense; Pyridones; Receptors, AMPA

Cognitive and psychiatric problems are common in people with epilepsy. They can have multiple causes, including structural brain lesions, the active epilepsy, and the effect of anti-epileptic therapy. Since patients' treatment compliance and quality of life are affected by cognitive and emotional status, it is crucial for clinicians to understand how anti-seizure medications (ASMs) affect cognition and mood, and to choose the proper ASM.. To conduct a literature review of the impact on cognition and mood status of lacosamide (LCM) in people with epilepsy.. Wesearched PubMed, the Cochrane Database of Systematic Reviews and reference lists of articles for all types of articles with no limitations on publication date.. A total of 251 records were obtained, including 247 articles in PubMed and 4 articles from reference lists. We included 2 meta-analyses, one randomized controlled trials and 14 observational studies after the screening process. Most studies agree LCM has low risk of treatment-emergent adverse events (TEAEs) on cognition. Comparisons with other ASMs, LCM may be preferable to carbamazepine, topiramate and perampanel, and not inferior to lamotrigine. In spite of low incident rate, depression is the most common psychiatric change of LCM. There are no consistent positive or negative psychiatric effects of LCM.. Lacosamide has limited impact on cognitive and mood status in this review. Several factors including mechanism of co-administration of ASMs and personal history of psychiatric disorder should be considered as important in the development of cognitive and psychiatric side effects. However, the heterogeneity between studies make the quality of evidence weaker and further trials are needed.

Topics: Adult; Affect; Anticonvulsants; Carbamazepine; Cognition; Epilepsy; Humans; Lacosamide; Lamotrigine; Nitriles; Pyridones; Quality of Life; Topiramate

Perampanel como terapia añadida precoz en el tratamiento de la epilepsia.

Topics: Adolescent; Adult; Anticonvulsants; Drug Synergism; Drug Therapy, Combination; Epilepsy; Gastrointestinal Diseases; Humans; Levetiracetam; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Sleepiness; Treatment Outcome; Young Adult

This article reviews the profile of perampanel, a novel noncompetitive α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist, and its role as a potential broad-spectrum antiepileptic drug in the treatment of epilepsy. For this narrative review, data were collected using specified search criteria. Articles reporting the evidence for perampanel's efficacy from preclinical models, phase 3 clinical studies, observational studies, and descriptive evidence were included. AMPA receptors play a key role in mediating the action of glutamate at the excitatory synapse. Preclinical research showed the AMPA receptor blockade to constitute a promising target for antiepileptic drug therapy. In animal models, perampanel proved to be protective against seizures and reduce seizure severity and duration. Four phase-3 randomized controlled trials (3 in patients with focal seizures and one in primary generalized tonic-clonic seizures in idiopathic generalized epilepsy) have been completed. In focal (partial) onset seizures, perampanel (4, 8, and 12 mg) significantly reduced seizure frequency per 28 days (23.3%-28.8% vs 12.8%; P < .01) and responder rates (≥50% reduction in seizures) (28.5%-35.3% vs 19.3%; P < .05) compared with placebo. In primary generalized tonic-clonic seizures, perampanel 8 mg resulted in greater reduction in seizure frequency per 28 days (-76.5% vs -38.4%; P < .0001) and responder rate (64.2% vs 39.5%; P = .0019) than placebo. The efficacy, safety, and tolerability of perampanel have been reproduced in real-world clinical practice, and the agent has been shown to be effective in other epilepsy syndromes. Perampanel is a potentially broad-spectrum antiepileptic drug with a novel mechanism of action that may be a useful addition for patients with epilepsy with various seizure types. The availability of novel antiepileptic drugs for epilepsy treatment enables more individualized treatment for these patients.

Topics: Anticonvulsants; Drug Resistant Epilepsy; Epilepsy; Humans; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Receptors, AMPA

Medical therapy is the mainstay of management of epilepsy. Despite the increasing number of available antiepileptic drugs (AEDs), approximately one-third of epileptic patients do not have adequate control of seizures. There is still a need for the development of new AEDs with enhanced effectiveness and tolerability. Areas covered: The present manuscript is based on an Internet and PubMed search (January 2005 to August 2018). It is focused on pharmacokinetic and clinical data of perampanel (PER) for the treatment of epilepsy. Expert opinion: PER has a novel mechanism of action, which opens up new options for a rational combination therapy. Phase III trials have demonstrated the efficacy and safety of PER as adjunctive therapy for the treatment of partial-onset seizures (POS) and primary generalized tonic-clonic seizures in patients aged ≥12 years. PER is also approved by FDA as monotherapy for the treatment of POS. A clinical trial is ongoing to verify the efficacy and safety of PER monotherapy in untreated patients with POS. In the future, head-to-head comparisons are needed to determine the exact position of PER relative to other AEDs. Moreover, further studies are needed to evaluate the efficacy and safety of PER in patients aged <12 years.. 4βOHC: 4β-hydroxycholesterol; AUC: area under the curve; CBZ: Carbamazepine; CLCr: creatinine clearance; Cmax: maximum plasma concentration; CYP: cytochrome P; EIAED: enzyme-inducing antiepileptic drug; EMA: European Medicines Agency; FDA: Food and Drug Administration; GI: gastrointestinal; OXC: oxcarbazepine; PER: perampanel; PGTC: primary generalized tonic-clonic; PHT: phenytoin; POS: partial-onset seizures; QD: once-daily; TEAE: treatment-emergent adverse event; Tmax: median time to reach peak concentration; UGT: uridine diphosphoglucose-glucuronosyltransferase; VPA: valproic acid.

Topics: Animals; Anticonvulsants; Child; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Topics: Anticonvulsants; Clinical Trials as Topic; Epilepsy; Half-Life; Humans; Nitriles; Pyridones; Pyrrolidinones; Receptors, AMPA; Status Epilepticus; Treatment Outcome

To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years).. Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction.. We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies.. This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria.

Topics: Adolescent; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Drug Resistant Epilepsy; Epilepsies, Partial; Epilepsy; Epilepsy, Absence; Ethosuximide; Hormones; Humans; Infant; Lamotrigine; Levetiracetam; Network Meta-Analysis; Nitriles; Odds Ratio; Piracetam; Pyridones; Spasms, Infantile; Treatment Outcome; Triazines; Valproic Acid

Antiepileptic drugs (AEDs) are effective against seizures, but their use is often limited by adverse effects, among them psychiatric and behavioral ones including aggressive behavior (AB). Knowledge of the incidence, risk factors, and the underlying mechanisms of AB induced by AEDs may help to facilitate management and reduce the risk of such side effects. The exact incidence of AB as an adverse effect of AEDs is difficult to estimate, but frequencies up to 16% have been reported. Primarily, levetiracetam (LEV), perampanel (PER), and topiramate (TPM), which have diverse mechanisms of action, have been associated with AB. Currently, there is no evidence for a specific pharmacological mechanism solely explaining the increased incidence of AB with LEV, PER, and TPM. Serotonin (5-HT) and GABA, and particularly glutamate (via the AMPA receptor), seem to play key roles. Other mechanisms involve hormones, epigenetics, and "alternative psychosis" and related phenomena. Increased individual susceptibility due to an underlying neurological and/or a mental health disorder may further explain why people with epilepsy are at an increased risk of AB when using AEDs. Remarkably, AB may occur with a delay of weeks or months after start of treatment. Information to patients, relatives, and caregivers, as well as sufficient clinical follow-up, is crucial, and there is a need for further research to understand the complex relationship between AED mechanisms of action and the induction/worsening of AB.

Topics: Aggression; Anticonvulsants; Epilepsy; Humans; Levetiracetam; Nitriles; Pyridones; Topiramate

Perampanel is among the latest AEDs approved, indicated for the treatment of partial-onset seizures with or without secondary generalization, and for primary generalized tonic-clonic seizures, in patients aged 12 years and older. This paper summarizes the clinical recommendations on the current role of perampanel in the treatment of pediatric epilepsies and future directions for research. The optimal dosage should be comprised between 4 and 12 mg/day, with 8 mg/day being the most common dosage used. The rate and severity of adverse events, including psychiatric symptoms, can be decreased by starting at low doses, and titrating slowly. Overall, perampanel presents an acceptable risk/benefit ratio, but special caution should be made to the risk of seizure aggravation and behavioral problems. The favorable cognitive profile, the ease of use of the titration scheme and the once-daily formulation offer advantage over other AEDs and make this drug particularly suitable for adolescent population. Perampanel is a welcome addition to the armamentarium of the existing AEDs, as it represents a new approach in the management of epilepsy, with a novel mechanism of action and a potential to have a considerable impact on the treatment of adolescents with epilepsy.

Topics: Adolescent; Anticonvulsants; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Female; Humans; Male; Nitriles; Patient Safety; Prognosis; Pyridones; Risk Assessment; Severity of Illness Index; Treatment Outcome

The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are the major mediators of glutamate-mediated excitatory neurotransmission, and are critical for synchronization and spread of epileptic activity. Areas covered: AMPA receptor antagonists have been also developed as antiepileptic drugs and perampanel (PER) is the first highly selective, non-competitive AMPA-type glutamate receptor antagonist that is available on the market. It is approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalization, and for primary generalized tonic-clonic seizures in idiopathic generalized epilepsy, in patients aged ≥ 12 years. This article reviews the role of AMPA receptors in the neuronal hyperexcitability underlying epilepsy, the mechanism of action and clinical experience on the anti-seizure activity of PER. Moreover, the rationale for targeting AMPA receptor in specific epileptic disorders, including brain tumor-related epilepsy, mesial temporal lobe epilepsy with/without hippocampal sclerosis, and status epilepticus is evaluated. Finally, the pharmacological rationale for the development of AMPA receptor antagonists in other neurological disorders beyond epilepsy is considered. Expert opinion: Further research aimed at better understanding the pharmacology and blocking mechanism of PER and other AMPA receptor antagonists will drive future development of therapeutic agents that target epilepsy and other neurological diseases.

Topics: Anticonvulsants; Brain Neoplasms; Epilepsy; Epilepsy, Generalized; Epilepsy, Temporal Lobe; Humans; Nitriles; Pyridones; Receptors, AMPA; Status Epilepticus

Perampanel is a first-in-class antiepileptic medication approved for the treatment of partial (focal) seizures, and as adjunctive treatment for primarily generalized tonic-clonic seizures. The pharmacology, efficacy data, adverse-effect profile, pharmacokinetics and place in therapy are reviewed.. Perampanel is indicated for use in patients with epilepsy who are 12 years of age or older. It is the first medication designed specifically to be a non-competitive antagonist at post-synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors. Efficacy in refractory seizures has been established, and ongoing efficacy demonstrated by post-marketing data. The drug is completely absorbed, and exhibits a half-life that allows for once-daily administration in doses up to 12 mg/day. Drug interactions are minimal, but increased doses may be necessary when given with strong inducers of cytochrome P450 enzymes, including when perampanel is co-administered with other antiepileptics that exhibit this property. The most common adverse effects noted in both clinical trials and post-marketing are dizziness and somnolence. Psychiatric and behavioral adverse events have been documented in both adult and pediatric patients, including those with no corresponding diagnostic history.. Perampanel is a novel adjunctive antiepileptic medication that is an effective option for adolescents and adults with partial seizures, and primarily generalized tonic-clonic seizures uncontrolled with other medications.

Topics: Adolescent; Adult; Anticonvulsants; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Seizures

The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2-12 mg); perampanel is 95% protein-bound to albumin and α1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.

Topics: Anticonvulsants; Drug Interactions; Epilepsy; Humans; Nitriles; Protein Binding; Pyridones; Receptors, AMPA

Perampanel (PER) has been tested in three randomized placebo-controlled prospective phase III trials as an adjunctive antiepileptic drug (AED) in adult and adolescent patients age 12 years and older who had ongoing focal epileptic seizures despite receiving one to three AEDs. Patients were randomized to once-daily placebo or maintenance dosages of 2, 4, or 8 mg of PER daily in one trial or to dosages of 8 and 12 mg of PER in the other two studies. Baseline and double-blind titration periods comprised 6 weeks each before a 12-week maintenance phase. Primary endpoints were median change in partial seizure frequency (baseline vs. double-blind phase), and the percentage of patients achieving >50% reduction in seizure frequency (so-called responders, baseline vs. maintenance). All patients had the opportunity to enter an open follow-up study that allowed a titration of PER of up to 12 mg. Pooled data of all three studies included 1,478 patients. There was a statistically significant median change in seizure frequency and responder rates with PER dosages of 4, 8, and 12 mg (p < 0.01, each dose vs. placebo). Both the results of each trial and the pooled data are reported in this review. For the open follow-up study, 1,218 patients were recruited. Ninety-one percent finally reached maintenance dosages of 10 or 12 mg. After 1 year, both median seizure reduction and responder rates reached almost 50%.

Topics: Anticonvulsants; Double-Blind Method; Epilepsy; Humans; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome

Quality of life is directly related to the number and severity of adverse effects, and a successful antiepileptic medication must demonstrate a good balance between efficacy and tolerability. Perampanel is a newly licensed antiepileptic medication for the adjunctive treatment of patients (age 12 and older) with partial epilepsy with or without secondary generalization. Safety endpoints in the three phase III trials (304, 305, and 306) included treatment-emergent adverse events (TEAEs), vital signs, clinical laboratory parameters, and electrocardiography studies (ECGs). The most common adverse drug reactions in patients receiving perampanel were dizziness, somnolence, fatigue, irritability, nausea, and falls. Of particular concern to patients are cognitive and psychiatric side effects. Overall, depression and aggression were reported more frequently in patients taking perampanel, particularly at higher doses, than in patients taking placebo. TEAEs necessitated the withdrawal of perampanel in 99 patients (9.5%) and placebo in 21 patients (4.8%). Typically this was due to dizziness, convulsion, and somnolence. There were no clinically important changes or treatment group differences in vital signs, ECG measures, or biochemical or hematologic parameters. Weight increase of greater than 7% was seen in 14.6% of perampanel-treated patients versus 7.1% of placebo-treated patients. Overall, perampanel appears to be associated with a relatively low incidence of serious adverse effects, particularly at low doses, and the majority of TEAEs were mild or moderate in intensity. The incidence of predictable side effects, such as somnolence and dizziness, is seen more frequently at higher doses. Of importance is the greater rate of psychiatric side effects in patients treated with perampanel, principally, irritability and aggression, than with placebo. However, the rate of serious psychiatric TEAEs was low.

Topics: Anticonvulsants; Dizziness; Epilepsy; Female; Humans; Male; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

In 2013, perampanel is approved as an add-on treatment for generalised and focal seizures in pharmaco-resistant epilepsy. New anticoagulants are superior to antivitamin K in stroke secondary prevention in case of atrial fibrillation. DBS remains a valid therapeutic option for advanced Parkinson's disease. Intranasal ketamine seems to reduce the intensity of severe migraine aura. High concentrations of topic capsaicin improve post-herpetic neuralgia. In Alzheimer's disease, statins might deteriorate cognitive functions. Oral immuno-modifing treatments for relapsing remitting multiple sclerosis have shown to slow cerebral atrophy progression at two years.

Topics: Central Nervous System Agents; Cerebrovascular Disorders; Deep Brain Stimulation; Epilepsy; Headache Disorders; Humans; Movement Disorders; Neurology; Neuromuscular Diseases; Nitriles; Pyridones

Perampanel is a novel AMPA receptor antagonist, approved in over 35 countries as an adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older (18 years and older in Canada). These countries include the members of the European Union, the USA, Canada and Switzerland. The AMPA receptor antagonist, perampanel, is the first approved antiepileptic drug to inhibit excitation of postsynaptic membranes through the selective inhibition of glutamate receptors.. This drug discovery case history focuses on the discovery and profiling of perampanel. It analyzes the pharmacological, behavioral and molecular mechanisms of perampanel and how they contribute to the therapeutic benefits of the drug. The article is based on the data reported in published preclinical and clinical studies, product labels and poster presentations.. Preclinical studies of perampanel have identified its broad-spectrum antiseizure effects in acute seizure models, with a narrow therapeutic index in the rotarod test similar to other AMPA receptor antagonists. This narrow therapeutic index is a potential problem for AMPA receptor antagonists. However, the discovery that perampanel has a very long half-life in humans, with gradual accumulation in plasma, could contribute to the development of tolerance. This, coupled with the identification of an optimal dosing strategy for individual patients, may help to maximize the utility of perampanel in the treatment of epilepsy.

Topics: Animals; Anticonvulsants; Epilepsy; Humans; Nitriles; Pyridones; Receptors, AMPA

Perampanel is a novel drug recently approved as adjunctive therapy in epileptic patients aged 12 years and older who have drug-resistant partial epilepsy with and without secondary generalization. Pharmacological researches revealed that perampanel reduces neuronal excitability by a non-competitive antagonistic activity against the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors causing modulation of glutamatergic neurotransmission. The pharmacological profile of the drug showed complete absorption following oral administration, and extensive metabolism in the liver by oxidation followed by glucuronidation with an elimination half-life of approximately 53-165 h (average: 105 h), allowing once-daily administration. Randomized placebo-controlled trials demonstrated an effective dose range of the drug, between 4 and 12 mg/day, to significantly reduce seizure frequency in patients with partial-onset seizure that are pharmacoresistant with a favorable tolerability profile. The most frequent adverse events of the drug reported in phase III clinical trials were dizziness, somnolence, fatigue, and headache. However, the data raised from the studies can give a hope that perampanel offers a valuable option as an adjuvant therapy for pharmacoresistant partial-onset and secondarily generalized seizures.

Topics: Anticonvulsants; Epilepsy; Humans; Nitriles; Pyridones; Receptors, AMPA

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors play a key role in mediating glutamatergic transmission in the cortex. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile) is a potent, orally active, highly selective, non-competitive AMPA-type glutamate receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories. Development of perampanel as adjunctive therapy for the treatment of partial-onset seizures was planned in keeping with regulatory guidance and guidelines on antiepileptic drug (AED) development. This is the first AED with a specific action on glutamate-mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment-refractory partial-onset seizures in Phase III clinical trials. Perampanel (Fycompa(®)) has been approved in the EU and the United States for adjunctive treatment of partial-onset seizures.

Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Drug Evaluation, Preclinical; Epilepsy; Humans; Nitriles; Pyridones

Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile; E2007] is a potent, selective, orally active non-competitive AMPA receptor antagonist developed for the treatment of epilepsy. Perampanel has a 2,3'-bipyridin-6'-one core structure, distinguishing it chemically from other AMPA receptor antagonist classes. Studies in various physiological systems indicate that perampanel selectively inhibits AMPA receptor-mediated synaptic excitation without affecting NMDA receptor responses. Blocking of AMPA receptors occurs at an allosteric site that is distinct from the glutamate recognition site. Radioligand-binding studies suggest that the blocking site coincides with that of the non-competitive antagonist GYKI 52466, believed to be on linker peptide segments of AMPA receptor subunits that transduce agonist binding into channel opening. As is typical for AMPA receptor antagonists, perampanel exhibits broad-spectrum antiseizure activity in diverse animal seizure models. Perampanel has high oral bioavailability, dose-proportional kinetics, and undergoes oxidative metabolism, primarily via CYP3A4, followed by glucuronidation. The terminal half-life (t½ ) in humans is 105 h; however, in the presence of a strong CYP3A4 inducer (such as carbamazepine), the t½ can be reduced. In sum, perampanel is a selective, centrally acting, negative allosteric modulator of AMPA receptors with good oral bioavailability and favorable pharmacokinetic properties.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Epilepsy; Excitatory Amino Acid Antagonists; Hippocampus; Mice; Neurons; Nitriles; Pyridones; Receptors, AMPA

The efficacy of adjunctive perampanel has been investigated in an extensive clinical development program across a broad, multinational population of patients with refractory partial-onset seizures. Further to the results of two Phase II dose-finding studies, perampanel was evaluated in three large Phase III registration studies at the predicted no-effect dose of 2 mg/day and the predicted effective doses of 4, 8, and 12 mg/day. In all three studies, perampanel 4, 8, and 12 mg/day consistently provided significant reductions in the frequency of partial-onset seizures compared with placebo. Improvements in responder rates and seizure freedom rates were also observed. In addition, data from recent interim analyses of extension studies have indicated that these efficacy outcomes may be maintained with long-term treatment. Overall, these studies form a solid evidence base to support the efficacy of adjunctive perampanel in the treatment of refractory partial-onset seizures.

Topics: Anticonvulsants; Clinical Trials as Topic; Dose-Response Relationship, Drug; Epilepsy; Humans; Nitriles; Pyridones; Treatment Outcome

To identify adverse events (AEs) significantly associated with perampanel treatment in double-blind clinical studies (RCTs). Serious AEs, study withdrawals due to AEs and dose-effect responses of individual AEs were also investigated.. All placebo controlled, double-blind RCTs investigating therapeutic effects of oral perampanel were searched. AEs were assessed for their association with perampanel after exclusion of synonyms, rare AEs and non-assessable AEs. Risk difference (RD) was used to evaluate the association of any AE (99% confidence intervals) and withdrawals or serious AEs (95% confidence intervals) with perampanel.. Nine RCTs (five in pharmacoresistant epilepsy and four in Parkinson's disease) were included in our study. Almost 4000 patients had been recruited, 2627 of whom were randomized to perampanel and treated with drug doses of 0.5 mg/day (n = 68), 1 mg/day (n = 65), 2 mg/day (n = 753), 4 mg/day (n = 1017), 8 mg/day (n = 431) or 12 mg/day (n = 293). Serious AEs were not significantly associated with perampanel treatment. The experimental drug was significantly associated with an increased risk of AE-related study withdrawals at 4 mg/day [RD (95% confidence interval) 0.03 (0.00, 0.06)] and 12 mg/day [RD (95% confidence interval) 0.13 (0.07, 0.18)]. Of 15 identified AEs, five (dizziness, ataxia, somnolence, irritability and weight increase) were found to be significantly associated with perampanel and one (seizure worsening) was significantly associated with placebo.. Vestibulocerebellar AEs (dizziness, ataxia), sedative effects (somnolence), irritability and weight increase were significantly associated with perampanel treatment.

Topics: Anticonvulsants; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Epilepsies, Partial; Epilepsy; Humans; Nitriles; Parkinson Disease; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Seizures

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic membrane are involved in fast excitatory signaling in the brain and their activation may lead to the firing of action potentials. Talampanel and perampanel were the first noncompetitive AMPA receptor antagonists to be tested as add-on drugs in patients with refractory partial seizures, and were found to be effective in improving seizure control. Due to an unfavorable kinetic and tolerability profile, talampanel clinical development in the field of epilepsy was discontinued early while perampanel has been recently approved in Europe and the USA as adjunctive therapy for adults with partial seizures with or without secondary generalization. The recommended perampanel starting dose is 2 mg/day once daily, which can be increased up to the recommended maintenance dose of 4-8 mg/day. Increments should be of 2 mg/day and based on clinical response and tolerability. Titration should be performed at 1-week intervals or at lower speed and a 12-mg daily dose should be considered after careful evaluation. To date, no serious and/or idiosyncratic adverse effects have been associated with this agent. Most frequently reported adverse effects are dizziness, ataxia, aggression, irritability, vertigo, somnolence, fatigue, headache and gait disturbance. Weight increase is the only non-neurological adverse effects associated with perampanel.

Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Epilepsy; Humans; Nitriles; Pyridones; Receptors, AMPA

Perampanel is a new chemical entity recently approved in the United States (US) and European Union (EU) as adjunctive treatment of partial-onset seizures with and without secondary generalization in patients with epilepsy aged 12 years and older. Pharmacological studies suggest that perampanel acts with a new mechanism of action via non-competitive antagonism of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor of glutamate, the main mediator of excitatory neurotransmission in the central nervous system. Perampanel is completely absorbed after oral administration. The drug is 95% bound to plasma proteins and is extensively metabolized by oxidation followed by glucuronidation. Perampanel has an elimination half-life of approximately 52-129h, allowing once daily dosing, with peak plasma levels observed 0.25-2h post-dose. Randomized placebo-controlled trials of adjunctive treatment have demonstrated that once-daily perampanel doses of 4-12mg/day significantly reduced partial-onset seizure frequency in patients with pharmacoresistant epilepsy along with a favorable tolerability profile. In perampanel pivotal trials, the most frequently reported treatment emergent adverse events (>10%) included dizziness, somnolence, fatigue and headache. Perampanel therapeutic response was maintained in patients included in the long term open-label extension studies for up to 4 years. Based on these data, perampanel offers a valuable option in the add-on treatment of partial-onset and secondarily generalized seizures.

Topics: Administration, Oral; Animals; Anticonvulsants; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Epilepsy; Humans; Molecular Structure; Nitriles; Pyridones; Treatment Outcome

This post hoc analysis evaluated whether continued treatment with perampanel monotherapy beyond initial titration may be appropriate for patients with focal-onset seizures (FOS) with currently untreated epilepsy to achieve seizure freedom with an effective dose.. Study 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study of perampanel monotherapy. Patients aged ≥12 years with untreated FOS received perampanel 4 mg/d in a 32-week Treatment Phase (6-week Titration and 26-week Maintenance Periods); in case of seizure(s) during Maintenance Period, patients could enter a 30-week Treatment Phase (4-week Titration and 26-week Maintenance Periods) to be up-titrated to perampanel 8 mg/d. The primary endpoint was seizure-freedom rate during Maintenance Period in the modified Intent-to-Treat (mITT) Analysis Set (patients who had ≥1 post-dose efficacy measurement during Maintenance Period); safety was monitored. This analysis of 4-mg/d efficacy data assessed the proportion of patients achieving seizure freedom during the Maintenance Period (responders) relative to patients with an early/later response (depending on seizure status during the Titration Period).. In the mITT population (n = 73), 46 patients were 4-mg/d responders; of whom, 37 (80.4%) were early responders and nine (19.6%) were later responders. The mean (standard deviation) percent reductions in FOS frequency from baseline at the end of the 4-mg/d Titration Period were 100.0% (0.0%; early responders) and 46.3% (97.3%; later responders). Among the 27 4-mg/d nonresponders, nine (33.3%) patients who had an early response experienced seizure(s) during the subsequent 4-mg/d Maintenance Period. Safety outcomes were similar, regardless of responder status, without new safety concerns.. Some patients with untreated FOS may benefit from continued treatment beyond initial titration of perampanel monotherapy to achieve seizure freedom, suggesting that it may not be appropriate to make treatment decisions to discontinue or switch from perampanel monotherapy solely based on seizure response before an effective dose has been reached.

Topics: Anticonvulsants; Child; Double-Blind Method; Epilepsy; Freedom; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care.. PROVE was a retrospective, non-interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure-freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme-inducing antiseizure medications (EIASMs).. Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24-month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent.. In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months.

Topics: Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

PROVE is a retrospective, phase IV study assessing retention, dosing, efficacy, and safety of perampanel when administered to patients during routine clinical care. We report an interim analysis of preadolescent (1 to <12 years) and adolescent (12 to <18 years) patients. Data were obtained from medical records of patients with epilepsy initiating perampanel after January 1, 2014; cut-off date for this analysis was October 10, 2018. Overall, 151 preadolescent and 183 adolescent patients were included. Retention rates following 24 months on perampanel were 42.5% (preadolescent subgroup; n = 31/73) and 55.7% (adolescent subgroup; n = 54/97). Treatment-emergent adverse events occurred in 53 (35.1%) preadolescent (most common: aggression, irritability, and somnolence) and 78 (42.6%) adolescent patients (most common: somnolence, aggression, and dizziness). These data indicate that daily oral doses of perampanel are generally well tolerated during routine clinical care, with favorable retention rates for ≤2 years, in patients aged 1 to <18 years.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Epilepsy; Humans; Infant; Nitriles; Pyridones; Retrospective Studies; Sleepiness; Treatment Outcome

Report final data from adolescent (12-<18 years) and adult (≥18 years) patients from PROVE (NCT03208660), a multicenter, retrospective, non-interventional, Phase IV study to assess retention, efficacy, safety, and dosing of perampanel in patients with epilepsy during routine clinical care.. Data were retrospectively collected from medical/pharmacy records of patients in the US initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary endpoints included median percent changes in seizure frequency, seizure-freedom rates, investigator's impression of seizure effect, and treatment-emergent adverse events (TEAEs).. The Safety Analysis Set (SAS) included 294 adolescents and 1157 adults (median maximum perampanel dose, 6.0 mg/day). In patients eligible for inclusion in the retention rate analysis, 24-month retention rates were 53.5% (n=91/170) in adolescents and 47.8% (n=354/741) in adults. In patients with available efficacy data during Months 10-12, median percent seizure frequency reductions were 79.3% (n=20) in adolescents and 70.8% (n=92) in adults. Most patients in the SAS with seizure-effect data experienced an improvement in seizures at the last follow-up time point (adolescents, 51.4% [n=128/249]; adults, 52.3% [n=506/967]). TEAEs occurred in 113 adolescents (38.4%; most common, aggression [6.5%]) and 512 adults (44.3%; most common, dizziness [9.2%]).. Perampanel demonstrated favorable retention rates and sustained efficacy (up to 2 years) in adolescent and adult patients during routine clinical care; no new safety signals were observed.. NCT03208660 (https://clinicaltrials.gov/ct2/show/NCT03208660).

Topics: Adolescent; Adult; Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

This post hoc analysis of four open-label extension (OLEx) studies evaluated the long-term efficacy and safety of adjunctive perampanel in adolescent patients (aged 12 to ≤17 years) with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS).. Patients who completed one of six double-blind, placebo-controlled studies could enter one of four OLEx studies comprising a blinded Conversion Period (6-16 weeks) followed by a Maintenance Phase (27 to ≤256 weeks; perampanel dose: ≤12 mg/day). Exposure, retention, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. Efficacy outcomes were analyzed using observed case and last observation carried forward (LOCF) approaches; the latter was used to account for early dropouts.. The Full Analysis Set comprised 309 adolescents with FOS (FBTCS, n = 109) and 19 with GTCS, and the Safety Analysis Set comprised 311 with FOS (FBTCS, n = 110) and 19 with GTCS. Mean (standard deviation) cumulative duration of perampanel exposure (weeks) was: FOS, 77.7 (58.7); FBTCS, 88.7 (63.8); and GTCS, 97.0 (35.5). Retention rates were maintained for ≤2 years (FOS, 50.0 %; FBTCS, 57.1 %; GTCS, 41.7 %). Seizure control (median percent reduction in seizure frequency/28 days) was sustained for up to 2 years; FOS (59.4 %, n = 113), FBTCS (64.6 %, n = 53), and GTCS (86.5 %, n = 17). At Year 2, 50 % responder rates were: FOS, 58.4 % (n = 66); FBTCS, 54.7 % (n = 29); and GTCS, 82.4 % (n = 14); seizure-freedom rates were: FOS, 5.3 % (n = 6); FBTCS, 24.5 % (n = 13); and GTCS, 35.3 % (n = 6). Long-term seizure control was observed even in LOCF analyses. The incidence of TEAEs was highest during Year 1 (FOS, n = 269 [86.5 %]; FBTCS, n = 95 [86.4 %]; GTCS, n = 15 [78.9 %]), compared with Years 2-4; the most common (≥10 % of patients) were dizziness, somnolence, and nasopharyngitis. No new safety signals emerged with long-term treatment.. This post hoc analysis suggests that long-term (≤2 years) adjunctive perampanel (≤12 mg/day) is efficacious and generally well tolerated in adolescent patients with FOS, with or without FBTCS, or GTCS.

Topics: Adolescent; Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Study 232, an open-label pilot study with an extension phase, evaluated the pharmacokinetics and preliminary safety/tolerability and efficacy of adjunctive perampanel oral suspension (≤0.18 mg/kg/d) in epilepsy patients aged ≥2 to <12 years. Patients were grouped into cohorts 1 (aged ≥7 to <12 years) and 2 (aged ≥2 to <7 years). The Core Study included pretreatment (≤2 weeks) and treatment phases (7-week titration; 4-week maintenance; 4-week follow-up [for those not entering the extension]). The extension phase consisted of 41-week maintenance and 4-week follow-up periods. Pharmacokinetic data were pooled with adolescent pharmacokinetic data from phase II/III studies. Population pharmacokinetic analysis showed that perampanel pharmacokinetics was independent of age, weight, or liver function, suggesting age- or weight-based dosing is not required and that the same dose can be given to adults and children to achieve exposures shown to be efficacious. Perampanel was well tolerated and efficacious for ≤52 weeks.

Topics: Administration, Oral; Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pilot Projects; Pyridones; Seizures; Treatment Outcome

To evaluate long-term tolerability, safety and efficacy of adjunctive perampanel in a Phase II, multicentre, open-label, dose-ascending Study 231 (NCT00849212) and its extension (Study 233; NCT00903786) in Japanese patients with refractory partial-onset seizures (POS), with/without secondarily generalised seizures.. In Study 231, patients received adjunctive perampanel ≤12 mg/day during a 10-week treatment period. Patients completing Study 231 could enter Study 233 (≤316-week treatment period). Assessments included monitoring of treatment-related treatment-emergent adverse events (TEAEs), median percent change in seizure frequency per 28 days, 50% responder and seizure-freedom rates. During Study 231, a pharmacokinetic analysis assessed the effects of enzyme-inducing antiepileptic drugs.. Overall, 23/30 (76.7%) patients completed Study 231; 21/30 (70.0%) received perampanel ≥8 mg/day and 10/30 (33.3%) achieved a maximum tolerated dose of 12 mg/day. Median percent change in seizure frequency per 28 days was -35.0%. 50% responder rate was 37.0%; 4 (13.3%) patients achieved seizure freedom. Twenty-one patients entered Study 233. Mean duration of exposure was 195 weeks; 9 (42.9%) patients received perampanel for ≤208 weeks. Seizure control was sustained for 316 weeks in 3/21 (14.3%) patients; 2 achieved seizure freedom. Treatment-related TEAEs were tolerable; the most common was dizziness (Study 231, 53.3%; Study 233, 14.3%). Mean perampanel plasma concentrations were lower with concomitant carbamazepine vs non-inducers (152.7 ng/mL vs 389.4 ng/mL across perampanel groups); small patient numbers for non-inducers (n = 2) should be considered when interpreting these data.. Adjunctive perampanel demonstrated a favourable safety profile and long-term tolerability in Japanese patients with refractory POS for ≤316 weeks.

Topics: Adult; Anticonvulsants; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Tolerance; Epilepsy; Female; Humans; Japan; Longitudinal Studies; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome; Young Adult

To analyze occurrence of falls among patients with partial seizures, with/without secondarily generalized seizures (SGS), and primary generalized tonic-clonic seizures (PGTCS) in the perampanel phase III clinical studies.. Studies 304, 305, and 306 randomized subjects (≥12 years) with drug-resistant partial seizures (with/without SGS) to perampanel 2, 4, 8, or 12 mg or placebo for double-blind treatment. The adverse event (AE) of falls was analyzed in the Safety Analysis Set (N = 1480). Study 332 randomized subjects aged ≥12 years with a diagnosis of PGTCS into perampanel 8 mg or placebo groups for double-blind treatment. In a systematic review of reported falls in the study 332 Safety Analysis Set (N = 163), falls were queried to establish whether each was seizure related; subjects with falls resulting from a seizure were not included in this analysis.. For studies 304/305/306, treatment-emergent falls occurred in 5.1% perampanel-treated versus 3.4% placebo-treated subjects with partial seizures. Exposure-adjusted rate for falls (falls/subject-month of exposure) was greater for total perampanel than for placebo (0.0175 vs. 0.0093) and was dose related for those receiving perampanel. In subjects with SGS, incidence of treatment-emergent falls was 4.3% in perampanel and 4.0% in placebo groups. Exposure-adjusted rates were 0.0169 and 0.0097 falls per subject-month of exposure in perampanel and placebo, respectively. For study 332, 2.5% perampanel-treated and 1.2% placebo-treated subjects with PGTCS had treatment-emergent falls that were not part of a seizure. Exposure-adjusted rates were 0.0169 and 0.0032 falls per subject-month of exposure in perampanel and placebo, respectively.. Results of the perampanel studies suggest that patients with epilepsy should be monitored due to the common risk of falls.

Topics: Accidental Falls; Adolescent; Adult; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome; Young Adult

Perampanel is a selective, noncompetitive AMPA receptor antagonist with demonstrated efficacy and tolerability in partial seizures in patients aged ≥ 12 years in Phase III studies. Post-hoc analysis of these studies was conducted to determine the efficacy and tolerability of perampanel based on the number of concomitant antiepileptic drugs (AEDs) at baseline, as well as to examine which baseline characteristics, if any, were predictors of efficacy. Efficacy parameters were based on the number of baseline AEDs, and logistic regression analyses were used to evaluate the association of demographic and baseline clinical factors with probability of ≥ 50% reduction in seizure frequency. Patients on 1 AED at baseline were significantly more likely to have reduced seizure frequency (P<0.02) and improved 50% responder rate (P<0.02) than patients on 3 AEDs at baseline. Secondarily generalized seizures at baseline, unknown etiology, and use of concomitant non-inducer AEDs were also established as positive predictors of efficacy (50% responder rate; P<0.01). Patients with more AEDs at baseline were associated with greater use of inducers (P<0.01), which may result in decreased exposure of perampanel in these patients and lower efficacy. Patients with 1 AED at baseline had a significantly shorter time since diagnosis compared with patients in the 3 (P<0.01) AEDs group, as well as a lower median seizure frequency at baseline compared to patients on 3 AEDs (P<0.05), suggesting that the reduced efficacy of perampanel with 3 AEDs may also be associated with the greater severity of seizures in the patient groups. The incidence of adverse events in perampanel-treated patients was similar regardless of the number of AEDs at baseline. Greater efficacy is predicted for patients receiving fewer concomitant AEDs when starting perampanel, as well as for those receiving concomitant treatment with AEDs that are not CYP3A4 enzyme-inducers, compared to patients treated with multiple concomitant AEDs. The results of this study provide additional information for clinicians considering adding perampanel to their patients' treatment regimen earlier rather than later, and offer evidence regarding the potential for increased efficacy with a decreased medication burden.

Topics: Adult; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Humans; Logistic Models; Male; Nitriles; Precision Medicine; Pyridones; Seizures; Severity of Illness Index; Treatment Outcome

Evaluate the impact of concomitant enzyme (CYP3A4)-inducer antiepileptic drugs (EIAEDs) on the efficacy and safety of perampanel in patients from the 3 phase-III clinical trials.. Patients with pharmacoresistant partial-onset seizures in the 3 phase-III clinical studies were aged 12 years and older and receiving 1 to 3 concomitant antiepileptic drugs. Following 6-week baseline, patients were randomized to once-daily, double-blind treatment with placebo or perampanel 8 or 12 mg (studies 304 and 305) or placebo or perampanel 2, 4, or 8 mg (study 306).. Treatment response assessed by median percent reduction in seizure frequency and responder rates improved with perampanel compared with placebo. However, at 8 and 12 mg, the treatment response was significantly greater in patients receiving non-EIAEDs. The treatment effect (perampanel-placebo) also demonstrated a dose-dependent increase in all patients. The overall incidence of treatment-emergent adverse events was similar regardless of the presence of EIAEDs. Occurrence of some adverse events, such as fatigue, somnolence, dizziness, irritability, was greater in patients receiving non-EIAEDs, as was discontinuation because of adverse events.. Perampanel shows efficacy and safety in the presence and absence of EIAEDs. As systemic exposure to perampanel increases, so does efficacy. Given the extensive metabolism of perampanel, systemic exposure is clearly reduced with concomitant administration of CYP3A4 inducers. This supports the strategy of dosing perampanel to clinical effect. Recognition of these pharmacokinetic interactions will be important in the optimization of this novel medication.. This study provides Class II evidence that 2 to 12 mg/d doses of perampanel reduced seizure frequency and improved responder rate in the presence and absence of EIAEDs.

Topics: Adult; Anticonvulsants; Cytochrome P-450 CYP3A Inducers; Disorders of Excessive Somnolence; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Interactions; Epilepsy; Fatigue; Female; Humans; Internationality; Male; Mental Disorders; Nitriles; Pyridones; Treatment Outcome

To further explore the impact of concomitant antiepileptic drugs (AEDs) on the efficacy and tolerability of adjunctive perampanel for focal epilepsy.. Data were pooled from three phase III trials of adjunctive perampanel in patients (≥12 years of age) with refractory partial-onset seizures. Concomitant AEDs were categorized according to whether or not they were enzyme-inducing AEDs (EIAEDs; known to reduce perampanel plasma concentrations) or sodium channel blockers (SCBs). Post hoc analyses assessed the impact of co-administration of non-EIAED SCBs and the overall number of concomitant AEDs on changes in seizure frequency, 50% responder rates, rates of treatment-emergent adverse events (TEAEs), and rates of discontinuation due to TEAEs, in patients randomized to receive daily placebo or perampanel 2, 4, 8, or 12mg.. Amongst 1480 randomized and treated patients, most were receiving two or more concomitant AEDs (n=1273, 86.0%), one or more EIAEDs (n=1083, 73.2%), and/or one or more SCBs (n=1203, 81.3%) at Baseline. The magnitude of seizure reduction appeared unaffected by the presence of non-EIAED SCBs, but lower in the presence of multiple AEDs. Frequency of TEAEs did not appear to be affected by the presence of non-EIAED SCBs or multiple AEDs.. Beyond the known interactions between perampanel and EIAEDs, perampanel efficacy appears to be unaffected by the use of concomitant non-EIAED SCBs, but may be reduced in the presence of multiple concomitant AEDs (possibly indicative of the presence of more refractory epilepsy). Nonetheless, with careful titration to balance efficacy and tolerability, perampanel may be combined with a range of AEDs, facilitating integration into treatment plans.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome; Young Adult

Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel α-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures.. Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70 years) who completed one of two randomized, placebo-controlled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2 mg increments of perampanel every 2 weeks to 12 mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424 weeks (~8 years). Interim analysis data cut-off date was 1 December, 2010.. Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4 years after study start), over a third (n = 53, 38.4%) remained on perampanel; 41.3% (n = 57) of patients had >3 years of exposure; and 13.0% (n = 18) had at least 4 years' exposure. Mean ± standard deviation (SD) duration of exposure was 116 ± 75 weeks and mean ± SD dose during the OLE Maintenance Period was 7.3 ± 3.3 mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28 days during open-label treatment was -31.5% (-99.2 to 512.2).. Long-term - up to 4 years - adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Female; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome; Young Adult

Topics: Anticonvulsants; Down Syndrome; Epilepsies, Myoclonic; Epilepsy; Humans; Nitriles; Pyridones; Treatment Outcome

Topics: Acetonitriles; Chromatography, High Pressure Liquid; Epilepsy; Humans; Reproducibility of Results; Solvents; Tandem Mass Spectrometry; United States

Antiseizure medications (ASMs) may affect nocturnal sleep and daytime vigilance. Perampanel (PER), a third-generation ASM, showed to improve nocturnal sleep in patients with epilepsy (PWE). Although ASMs can have beneficial effects on nocturnal sleep and daytime sleepiness, no study investigated the effect of PER on both sleep-wake cycle and daytime sleepiness. Therefore, this study aimed to objectively evaluate the sleep-wake cycle and daytime sleepiness in PWE treated with PER as adjunctive therapy.. This prospective study included adult PWE who received PER as add-on treatment. Sleep-wake cycle was assessed through actigraphic monitoring and daytime sleepiness by the multiple sleep latency test (MSLT) performed at the end of the actigraphic recording. All patients performed both tests at baseline and at 6-month follow-up.. Ten patients (mean age: 44.50 ± 22.71 years, 50.0% female) were included. The mean monthly seizure frequency was 3.20 ± 5.94. Six of ten patients started PER as a first add-on treatment. The final PER dose was 5.11 ± 2.02 mg/day, and nine of ten patients achieved seizure freedom at follow-up. There was a significant decrease in mean monthly seizure frequency from baseline to follow-up (p = 0.004). No significant changes were found in the sleep-wake cycle parameters. An increase in sleep latency mean was observed at MSLT at 6-month follow-up (p = 0.005).. This study confirms that adjunctive PER is effective on seizures without pathologically change of the sleep-wake cycle in PWE and can even improve daytime sleepiness. This effect can be mediated by the achievement of seizure control. Therefore, PER may be promising in PWE with sleep disturbances and daytime sleepiness.

Topics: Adult; Aged; Disorders of Excessive Somnolence; Epilepsy; Female; Humans; Male; Middle Aged; Prospective Studies; Seizures; Sleep; Young Adult

Perampanel (PER) is an oral antiepileptic drug and its concomitant use with carbamazepine (CBZ) leads to decreased PER concentrations. However, the magnitude of its influence may vary, depending on the dynamics of the enzyme induction properties of CBZ. This study aimed to develop a population pharmacokinetic (PPK) model considering the dynamics of enzyme induction and evaluate the effect of CBZ on PER pharmacokinetics.. We retrospectively collected data on patient background, laboratory tests, and prescribed drugs from electronic medical records. We developed 2 PPK models incorporating the effect of CBZ-mediated enzyme induction to describe time-concentration profiles of PER using the following different approaches: (1) treating the concomitant use of CBZ as a categorical covariate (empirical PPK model) and (2) incorporating the time-course of changes in the amount of enzyme by CBZ-mediated induction (semimechanistic PPK model). The bias and precision of the predictions were investigated by calculating the mean error, mean absolute error, and root mean squared error.. A total of 133 PER concentrations from 64 patients were available for PPK modelling. PPK analyses showed that the co-administration of CBZ increased the clearance of PER. Goodness-of-fit plots indicated a favorable description of the observed data and low bias. The mean error, mean absolute error, and root mean square error values based on the semimechanistic model were smaller than those obtained using the empirical PPK model for predicting PER concentrations in patients with CBZ.. We developed 2 PPK models to describe PER pharmacokinetics based on different approaches, using electronic medical record data. Our PPK models support the use of PER in clinical practice.

Topics: Benzodiazepines; Carbamazepine; Drug Interactions; Enzyme Induction; Epilepsy; Humans; Retrospective Studies

To explore the relationship between the proinflammatory factor high-mobility group box 1 (HMGB1) and glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the development of epilepsy.. Thalamic reticular nucleus (TRN) slices were treated with kainic acid (KA) to simulate seizures. Action potentials and spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded within TRN slices using whole-cell patch clamp techniques. The translocation of HMGB1 was detected by immunofluorescence. The HMGB1/TLR4 signaling pathway and its downstream inflammatory factors (IL-1β and NF-κB) were detected by RTPCR, Western blot and ELISA.. KA-evoked spikings were observed in TRN slices and blocked by perampanel. sIPSCs in the TRN were enhanced by KA and reduced by perampanel. The translocation of HMGB1 in the TRN was promoted by KA and inhibited by perampanel. The expression of the HMGB1/TLR4 signaling pathway was promoted by KA and suppressed by perampanel.. KA induced hyperexcitability activates the HMGB1/TLR4 pathway, which potentially leading to neuroinflammation in epilepsy.

Topics: Epilepsy; HMGB1 Protein; Humans; Kainic Acid; NF-kappa B; Receptors, AMPA; Toll-Like Receptor 4

Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy.. This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified.. A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity.. Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.

Topics: Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Glutamic Acid; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Protocadherins; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Topics: Animals; Anticonvulsants; Astrocytes; Epilepsy; Nitriles; Pyridones; Rats; Receptors, AMPA; Seizures; Treatment Outcome

Patients with epilepsy often show treatment-related psychiatric symptoms. Among the novel antiseizure medications (ASM), Perampanel (PER), Levetiracetam (LEV), and Topiramate (TPM) have been reported to have a relatively high frequency of psychiatric adverse events. However, these psychiatric symptoms are not identical; PER and LEV show adverse events of irritability and aggression, while TPM shows typical symptoms of depression and schizophrenia. It is important to understand the characteristics of these psychiatric adverse events to design appropriate treatment regimens for epileptic patients. (Received August 1, 2022; Accepted December 24, 2022; Published April 1, 2023).

Topics: Anticonvulsants; Epilepsy; Humans; Levetiracetam; Mental Disorders; Topiramate

Early-life seizures can be refractory to conventional antiseizure medications (ASMs) and can also result in chronic epilepsy and long-term behavioral and cognitive deficits. Treatments targeting age-specific mechanisms contributing to epilepsy would be of clinical benefit. One such target is the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subtype of excitatory glutamate receptor, which is upregulated in the developing brain. Perampanel is a non-competitive, selective AMPAR antagonist that is FDA-approved for focal onset seizures (FOS) or primary generalized tonic-clonic seizures (PGTC) in children and adults. However, the efficacy of perampanel treatment in epilepsy patients younger than 4 years has been less documented. We thus tested the efficacy of perampanel in two early-life seizure models: (1) a rat model of hypoxia-induced neonatal seizures and (2) a mouse model of Dravet syndrome with hyperthermia-induced seizures. Pretreatment with perampanel conferred dose-dependent protection against early-life seizures in both experimental models. These findings suggest that AMPAR-mediated hyperexcitability could be involved in the pathophysiology of early-life seizures, which may be amenable to treatment with perampanel.

Topics: Animals; Anticonvulsants; Epilepsy; Mice; Pyridones; Rats; Rodentia; Treatment Outcome

Antiseizure medication (ASM) as monotherapy or in combination is the treatment of choice for most patients with epilepsy. Therefore, knowledge about the typical adverse events (AEs) for ASMs and other coadministered drugs (CDs) is essential for practitioners and patients. Due to frequent polypharmacy, it is often difficult to clinically assess the AE profiles of ASMs and differentiate the influence of CDs.. This retrospective analysis aimed to determine typical AE profiles for ASMs and assess the impact of CDs on AEs in clinical practice.. The Liverpool AE Profile (LAEP) and its domains were used to identify the AE profiles of ASMs based on data from a large German multicenter study (Epi2020). Following established classifications, drugs were grouped according to their mode of action (ASMs) or clinical indication (CDs). Bivariate correlation, multivariate ordinal regression (MORA), and artificial neural network (ANNA) analyses were performed. Bivariate correlation with Fisher's z-transformation was used to compare the correlation strength of LAEP with the Hospital Anxiety and Depression Scale (HADS) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to avoid LAEP bias in the context of antidepressant therapy.. Data from 486 patients were analyzed. The AE profiles of ASM categories and single ASMs matched those reported in the literature. Synaptic vesicle glycoprotein 2A (SV2A) and voltage-gated sodium channel (VGSC) modulators had favorable AE profiles, while brivaracetam was superior to levetiracetam regarding psychobehavioral AEs. MORA revealed that, in addition to seizure frequency, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators and antidepressants were the only independent predictors of high LAEP values. After Fisher's z-transformation, correlations were significantly lower between LAEP and antidepressants than between LAEP and HADS or NDDI-E. Therefore, a bias in the results toward over interpreting the impact of antidepressants on LAEP was presumed. In the ANNA, perampanel, zonisamide, topiramate, and valproic acid were important nodes in the network, while VGSC and SV2A modulators had low relevance for predicting relevant AEs. Similarly, cardiovascular agents, analgesics, and antipsychotics were important CDs in the ANNA model.. ASMs have characteristic AE profiles that are highly reproducible and must be considered in therapeutic decision-making. Therapy using perampanel as an AMPA modulator should be considered cautiously due to its relatively high AE profile. Drugs acting via VGSCs and SV2A receptors are significantly better tolerated than other ASM categories or substances (e.g., topiramate, zonisamide, and valproate). Switching to brivaracetam is advisable in patients with psychobehavioral AEs who take levetiracetam. Because CDs frequently pharmacokinetically interact with ASMs, the cumulative AE profile must be considered.. DRKS00022024, U1111-1252-5331.

Topics: Adult; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Anticonvulsants; Epilepsy; Humans; Levetiracetam; Retrospective Studies; Topiramate; Valproic Acid; Zonisamide

The efficacy of perampanel (PER) in pediatric epilepsy with specific etiologies has not been well established. Here, we investigated outcome and predictors of PER treatment in a pediatric cohort with known and presumed genetic etiology.. We included pediatric patients with potential genetic epilepsy who received PER treatment and underwent whole-exome sequencing (WES) from January 2020 to September 2021. All patients were followed up for >12 months.. A total of 124 patients were included. Overall response rates were 51.6% and 49.6% at 6 months and 12 months, respectively. Pathogenic or likely pathogenic variants in 27 multiple genes were detected among 58 patients (46.8%) by WES. On performing multivariate logistic regression analysis, only developmental delay (OR = 0.406, P = 0.042) was a negative predictor of treatment response. However, the seizure onset age, positive WES results, and number of ASMs before PER administration were not significantly. Thirteen carriers with variants in the SCN1A gene showed a better response compared to eight patients with other sodium channels (P = 0.007), and to the other 45 patients with positive WES results (OR = 7.124, 95% CI = 1.306-38.860, P = 0.023). Adverse events were only reported in 23 patients, the most common being emotional problems.. PER is safe and efficacious in pediatric patients with known and presumed genetic etiology. The response rate is comparable to that reported in other pediatric populations, and lower among those with developmental delay. A gene-specific response to PER is found along with better efficacy links to pathogenic variants in the SCN1A gene.

Topics: Causality; Child; Epilepsy; Humans; Pyridones; Seizures

Topics: Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Humans; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Perampanel is an oral anti-seizure medication, which is approved in Japan for focal-onset seizures, with/without focal to bilateral tonic-clonic seizures, as monotherapy/adjunctive therapy in patients aged 4 years and older. Treatment for generalized tonic-clonic seizures as adjunctive therapy in patients aged 12 years and older is approved as well. We evaluated the feasibility of intravenous (IV) administration of perampanel as an alternative to oral administration.. Study 240 (NCT03754582) was an uncontrolled, open-label study of IV perampanel, conducted in 21 Japanese patients with epilepsy who received a stable dose of 8-12 mg/day of oral perampanel. Patients received 30-minute IV infusions at equivalent daily doses of oral perampanel for 4 days, then were switched back to oral perampanel. Safety, tolerability, plasma concentration, and maintenance of efficacy throughout the transition between IV and oral dosing of perampanel were assessed. As supportive data, a subgroup analysis was also conducted using data from healthy Japanese subjects (n = 18) who were enrolled in Study 050 (NCT03376997) investigating the pharmacokinetics and safety of IV perampanel in healthy subjects who received an IV infusion (30-, 60-, or 90-minute) of perampanel 12 mg and a single oral administration of perampanel 12-mg tablet.. In Study 240, the transition between 30-minute IV and oral perampanel dosing was associated with a ≤1.4-fold increase in the mean change in maximum observed concentration of perampanel. Seizure outcomes demonstrated no considerable changes in efficacy before, during, or after 30-minute IV dosing of perampanel. The safety profiles were similar between IV and oral formulations. In Study 050, the pharmacokinetics of 30- or 60-minute IV infusion of perampanel further support the interchangeability between oral and IV formulations in the Japanese subjects.. These results support that 30-minute IV perampanel may be a potential short-term alternative to oral formulations for patients with epilepsy.

Topics: Administration, Intravenous; Anticonvulsants; East Asian People; Epilepsy; Humans; Treatment Outcome

This study determined the 24-month outcomes of perampanel treatment in children and adolescents with epilepsy. The percentage of ≥ 50% responders was 47.3% (139/294) at 12 months and 49.0% (144/294) at 24 months. A 100% reduction in seizures for more than 12 months was observed in 12.2% (36/294). Discontinuation occurred in 39.8% (117/294). The most common reason for discontinuation was adverse events (29.1%, 34/117). Baseline seizure frequency was higher in children aged < 12 years than in patients aged ≥ 12 years; however, the percentage of seizure reduction and ≥ 50% responders did not significantly differ between the two groups. The rate of early discontinuation was higher (p < 0.001) and the duration of perampanel treatment was shorter in children aged < 12 years (p = 0.001). Most children aged < 12 years discontinued PER due to inadequate effectiveness, while adverse event was the most common reason in patients aged ≥ 12 years (p = 0.045). Only slow titration was significantly associated with ≥ 50% of responders. In conclusion, this study showed that perampanel can be utilized effectively and safely for a prolonged period in pediatric patients aged 4 to < 12 years, as well as in patients aged 12 years and older.

Topics: Adolescent; Child; Dental Care; Epilepsy; Humans; Pyridones; Seizures

Poor medication adherence contributes to increased morbidity and mortality in patients with epilepsy and may be under-addressed in clinical practice. Ethical concerns make it impossible to study the impact of medication nonadherence in clinical trials, but our previous work emphasizes the importance of using preclinical approaches to address these questions. With over 30 clinically available antiseizure medicines (ASM's), it remains an important question to understand the relationship between poor adherence and seizure incidence across mechanistically distinct ASM's, including the broad-spectrum ASM, perampanel (PER).. We formulated PER into chow pellets to deliver to rats in a 100% fully adherent or 50% variable nonadherent paradigm via our novel automated medication-in-food delivery system. Chronic oral dosing was initiated in male rats with chronic epilepsy while monitoring 24/7 for videoEEG evidence of seizures during a 4-week placebo baseline and 4-week treatment phase. PER concentrations were monitored in plasma at 1-week intervals and correlated with degree of seizure control. The relationship between missed doses and extended patterns of nonadherence were correlated with breakthrough seizures.. Fully adherent rats demonstrated a median reduction in seizure frequency of 50%, whereas nonadherent rats had a median increase of 54%. Plasma concentrations of PER were stable over the 4-week treatment period in both fully adherent and nonadherent groups, with levels being twice as high in fully adherent animals. There was no correlation between a single missed dose or series of missed doses and the incidence of breakthrough seizures. However, those animals in the nonadherent group that received PER for every meal during a 24-h period had a reduced likelihood of seizure incidence.. If our preclinical data is supported in the clinic, PER's favorable pharmacokinetic profile in humans, combined with a lowered risk of breakthrough seizures suggests that it may provide a certain forgiveness factor if a dose is missed within a 24-h window.

Topics: Animals; Epilepsy; Forgiveness; Humans; Male; Medication Adherence; Rats; Seizures

This retrospective, observational study used US claims data to assess retention rates on cenobamate compared with four branded antiseizure medications (ASMs) in patients with epilepsy.. Adults (≥18 years) with prevalent epilepsy (ICD-10 code G40.xx) and ≥ 1 prescription for cenobamate or any of the newer branded ASMs (brivaracetam, eslicarbazepine, lacosamide, or perampanel) between May 1, 2020 and December 31, 2021 were identified from the HealthVerity Marketplace database. At least 360 days of continuous enrollment was required before and after the index date (Day 1 of initiating cenobamate or branded ASM). Patients were followed until cessation of cenobamate or branded ASM or the end of data collection using Kaplan-Meier methods. Retention was compared between cenobamate and the branded ASMs (both as a group and individually) using Chi-square tests.. In total, 4109 patients were included (195 cenobamate; 3914 branded ASMs). A higher proportion of patients in the cenobamate group compared with the branded ASMs group had concurrent focal and generalized epilepsy (65.6% vs 40.0%) and were on ≥ 3 concomitant ASMs (48.2% vs 12.8%) at the index date. Median time to discontinuation (i.e., the time that half the patients discontinued) was not quite reached after 12 months in the cenobamate group (50.3% of patients remained on cenobamate) and was 7.7 months in the branded ASMs group. Retention was significantly higher with cenobamate vs the branded ASMs group (p = 0.04545) and vs the individual ASMs lacosamide (p = 0.03044) and perampanel (p = 0.01558). Twelve-month retention rates (95% confidence intervals) were 50.3% (43.1%-57.0%) for cenobamate, 40.5% (38.9%-42.0%) for branded ASMs overall, 42.3% (38.6%-46.0%) for brivaracetam, 44.1% (39.2%-49.0%) for eslicarbazepine, 39.9% (38.0%-41.8%) for lacosamide, and 36.8% (31.9%-41.8%) for perampanel.. In this real-world analysis, retention was significantly higher with cenobamate vs a pooled group of four branded ASMs despite a greater frequency of patients in the cenobamate group having characteristics of more difficult-to-treat epilepsy.

Topics: Adult; Anticonvulsants; Epilepsy; Humans; Lacosamide; Retrospective Studies; Treatment Outcome; United States

Epilepsy is a neurological disease with high global prevalence. Almost one-third of epilepsy patients continue having seizures despite adequate treatment. Perampanel has been widely used in the Western countries as an adjunctive therapy for both generalized and focal seizures. Owing to its high cost, the use of perampanel is limited in our country.. We conducted a descriptive, retrospective study among epilepsy patients treated with perampanel. We aimed to assess the efficacy and safety of perampanel as an adjunctive in our hospital.. From our cohort of 25 patients, most of the patients were either on one or three anti-seizure medications (ASMs) prior to initiation of perampanel. Perampanel was added in 88% of them due to persistent seizures. Twenty-two (88%) patients experienced reduction in seizure frequency. 12% experienced mild side effects, which were leg cramps, hyponatremia and drowsiness. Only 1 patient stopped perampanel due to its side effects.. Perampanel is a well-tolerated ASM that should be widely used as an adjunctive. More studies with regards to its efficacy and safety involving more centres are encouraged in Malaysia.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Retrospective Studies; Treatment Outcome

Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke.. Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records.. Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs).. Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy.. This study was registered at ClinicalTrials.gov (NCT05267405).

Topics: Aged; Anticonvulsants; Benzodiazepines; Epilepsy; Humans; Ischemic Stroke; Lacosamide; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Topiramate; Zonisamide

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well-tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.

Topics: Anticonvulsants; Drug Resistant Epilepsy; Epilepsy; Excitatory Amino Acid Antagonists; Humans; Malformations of Cortical Development; Nitriles; Pyridones; Receptors, AMPA

While previous studies have demonstrated the safety and effectiveness of perampanel (PER) in combination with other anti-seizure medications in adult patients, data for older patients are limited. This study aimed to confirm real-world safety and effectiveness of combination treatment with PER in Japanese patients with focal seizures with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalised tonic-clonic seizures (GTCS) according to age subgroups (<65 and ≥65 years of age).. This large-sample prospective post-marketing observational study included a 24-52-week observation period after the first PER treatment. Safety was assessed according to adverse drug reactions (ADRs) and efficacy was evaluated based on the 50% responder rate and rates of overall symptom improvement.. Among the 3,808 patients who were enrolled, 3,716 (3,026 patients aged <65 years and 690 patients aged ≥65 years) and 3,272 were included in the safety and efficacy analysis datasets, respectively. ADRs were reported for 1,247 patients (33.6%) in the safety analysis dataset. Of these, 36.2% and 22.2% were aged <65 years and ≥65 years, respectively, and the most common ADRs were somnolence (11.6%, 5.5%) and dizziness (9.7%, 5.4%). The 50% responder rates in patients aged <65 years and those ≥65 years were 60.1% and 89.0% for those with focal aware seizures (FAS) with motor signs; 48.0% and 60.0% for FAS without motor signs; 47.4% and 80.2% for focal impaired awareness seizures; 70.8% and 93.4% for FBTCS; and 63.6% and 88.9% for GTCS, respectively. The improvement rates of symptoms/conditions were also higher in patients aged ≥65 years than those <65 years.. PER was effective in reducing seizure frequency and was safe, especially in older patients. PER may be a clinical treatment option for older patients with seizure disorders.

Topics: Aged; Anticonvulsants; Epilepsy; Humans; Japan; Middle Aged; Nitriles; Prospective Studies; Pyridones; Seizures; Treatment Outcome

Aggression is the most commonly encountered antiepileptic-drug (AED)-induced psychiatric adverse effects. Levetiracetam (LEV) is well known to be associated with increased rates of aggression, while perampanel (PER) is also recognized as a potentially aggression-promoting agent, though opinions vary. However, few studies have addressed questions regarding whether the nature of irritability-aggression differs between those drugs. The present study used a standardized rating scale to examine aggression among patient with epilepsy who received LEV or PER using specific measures to confirm the effects of the drugs.. We enrolled 144 consecutive outpatients receiving treatment for epilepsy with LEV (n = 103) or PER (n = 41), and determined their effects regarding aggression using the Buss-Perry Aggression Questionnaire (BAQ). For analysis, total BAQ scores for the LEV and PER subjects were compared to determine whether the aggression-promoting effects of the agents differed, and which BAQ subdomains (physical aggression, verbal aggression, anger, hostility) were related to production of aggression in patients taking either LEV or PER. As a subsidiary analysis, clinical variables inclusive of administered AED type that showed a significant impact on BAQ scores were determined.. The LEV group had a significantly higher hostility score (19.4 ± 5.8) as compared to the PER group (17.2 ± 6.3) in subscale analysis (p < 0.05). In multiple regression analysis, LEV had a significant association with higher hostility score (P = 0.006).. Our results indicate that while easily visible outward-directed aggression tends to be dominant in patients given PER, aggression provoked by LEV may be felt more subjectively or in an inward-directed manner, which can lead to more diverse expression and misrecognition.

Topics: Aggression; Anticonvulsants; Epilepsy; Humans; Levetiracetam; Nitriles; Pyridones

Perampanel is a once-daily oral anti-seizure medication for focal-onset seizures, with or without focal to bilateral tonic-clonic seizures (FBTCS), and generalized tonic-clonic seizures. Study 402 (NCT02033902) collected safety information on clinically important treatment-emergent adverse events (TEAEs) from real-world clinical practice in patients aged ≥12 years with refractory epilepsy who were receiving perampanel as an add-on therapy.. Study 402 was a multicenter, observational, 52-week cohort study conducted in Austria, Belgium, Czech Republic, Denmark, France, Israel, Sweden, and the United Kingdom. Safety data were gathered prospectively from patients at clinic visits. The primary endpoint was the incidence of clinically important TEAEs defined as dizziness; blurred vision; somnolence; aggression; balance disorders (including ataxia and falls); weight gain; suicidality; drug abuse, misuse, dependence, and withdrawal; skin photosensitivity; and unintended pregnancy while taking levonorgestrel-containing contraceptives. Off-label use of perampanel and outcomes associated with any suspected drug-drug interaction were also monitored and recorded. Secondary endpoints included the Hospital Anxiety and Depression Scale (HADS) and Clinical Global Impression of Change.. Of 483 patients in the Safety Analysis Set, mean (standard deviation [SD]) age was 38.3 (15.1) years, 48.4% were female, mean (SD) time since diagnosis was 23 (14.8) years, 56.5% had focal impaired awareness seizures, and 48.7% had FBTCS. Overall, 243 (49.3%) patients treated with perampanel completed the study and 227 (46.0%) patients discontinued. The most common primary reason for discontinuation was adverse events (n = 130 [26.4%]). A total of 301 (62.3%) patients reported at least one TEAE, of which 45 (15.0%) patients had severe TEAEs and 256 (85.0%) patients had TEAEs judged as mild to moderate in severity. Overall, 51 (10.6%) patients had serious TEAEs, including two deaths that were judged as not related to perampanel, and 136 (28.2%) patients experienced a TEAE that led to treatment discontinuation. Clinically important TEAEs were reported by 153 (31.7%) patients, with the most common being dizziness (13.9%), balance disorders (5.6%), aggression (5.4%), and weight gain (5.4%). In general, the frequencies of clinically important TEAEs were lower in this study compared with previous interventional clinical studies, except for the incidence of suicidality (2.1% vs 1.0%) and aggression (5.4% vs 5.1%). Mean total HADS scores were similar at the end of the study compared with baseline; at the end of treatment, most (>60%) patients had no shift in HADS score category; ∼15% of patients moved to a worse category vs baseline and ∼20% of patients moved to an improved category vs baseline for both anxiety and depression. Based on investigator assessment, disease severity was improved in 185/415 (44.6%) patients. A subanalysis in elderly patients aged ≥65 years showed similar results to the overall population.. The data from this observational study are consistent with the known safety profile of perampanel derived from previous interventional phase II and III clinical studies. No unusual or unexpected TEAEs were observed in this real-world clinical practice setting.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Cohort Studies; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Humans; Nitriles; Pyridones; Treatment Outcome

Real-world data from adolescents treated with perampanel in a routine clinical setting are lacking in Japan. We evaluated the safety and efficacy of perampanel for adolescent patients (aged 12-17 years) with drug-resistant, refractory epilepsy in real-world settings.. This was a large-scale, prospective, observational post-marketing study, with a 104-week observation period. Safety was assessed by monitoring adverse effects (adverse drug reactions). For efficacy assessments, seizure frequency was compared between the four weeks immediately prior to the last observation and the four weeks before the commencement of perampanel.. In total, 519 patients were enrolled; 505 and 484 patients were included in the safety and efficacy analysis sets, respectively. The mean age was 14.4 years. The mean daily dose of perampanel was 4.4 mg/day. The main reasons for discontinuation at 104 weeks were adverse events (48.4%) and inadequate efficacy (46.8%). The retention rate at 104 weeks was 50.5%. Adverse effect and severe adverse effect incidences were 42.2% and 1.8%, respectively. The most common adverse effects were somnolence (13.5%), irritability (8.5%), dizziness (5.1%), and agitation (4.8%). There were significant differences in the occurrence of adverse effects between the initial titration interval of <2 weeks and 2-4 weeks (odds ratio=0.441, p=0.029) and 4-8 weeks (odds ratio=0.462, p=0.027). The median percent change in seizure frequency at the last observation carried forward was −50.0 for focal aware seizures with motor signs, −73.3 for focal aware seizures without motor signs, −28.6 for focal impaired awareness seizures, −62.6 for focal to bilateral tonic-clonic seizures, and −20.0 for generalized tonic-clonic seizures.. In adolescent patients, perampanel was well tolerated and efficacious in reducing seizure frequency. No unexpected safety issues were observed, and slow titration may reduce the incidence of adverse effects.

Topics: Adolescent; Drug Resistant Epilepsy; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Epilepsy; Humans; Japan; Nitriles; Prospective Studies; Pyridones; Seizures

This study has developed and validated a novel LC-MS/MS assay method to quantify perampanel in pediatric patients with epilepsy in Xinjiang, China. Our assay reduces current specimen volume requirements and decreases the turnaround time for results. Samples were separated by gradient elution and then injected into the mass spectrometer with a total run time of 3 min per sample. The ions from the analytes were detected using multiple reactions by monitoring transitions of m/z 350.2-219.0 for perampanel and m/z 359.1-323.1 for the internal standard, as precursor ion and product ion, respectively. The peak area ratios of perampanel with internal standard within the plasma samples were linear in the concentration range of 0.1-3.2 μg/mL (y = 2.87x + 0.61; r

Topics: Child; Chromatography, High Pressure Liquid; Chromatography, Liquid; Epilepsy; Humans; Nitriles; Pyridones; Reproducibility of Results; Tandem Mass Spectrometry

To evaluate the effectiveness and tolerability of perampanel (PER) in real-world settings in patients between 1 month and 18 years of age with drug resistant epilepsy (DRE) waiting for epilepsy surgery.. In this multicenter study, patients between 1 month and 18 years of age with DRE treated with PER between January 2020 and June 2021 were selected. The study outcome was effectiveness of PER treatment reported as reduction in seizure frequency and seizure freedom rate. Effectiveness was assessed at 30, 60, 90, 120, 150 and 180 days after initiation of PER. Tolerability profiles were reported as adverse events according to the observations of the patients' family members and physician.. Eighty-five patients treated with PER were included in the study. The mean initial dose and mean maximum dose of adjunctive PER was 2 mg/day and 5.8 mg/day, respectively. The mean seizure frequency (rate/week) was 41.3, 25.4, 18.9, 14.3, 11.2, 11.1 and 8.9 seizures at baseline, 30, 60, 90, 120, 150 and 180 days, respectively; the reduction in the mean seizure frequency at all timepoints was significant compared at the baseline (p<0.001). At 180 days, ≥75% seizure reduction was seen in 64.9% (37/57) of the patients and seizure freedom was achieved in 36.8% (21/57). Drowsiness, ataxia, and behavioral changes were the common adverse events observed, and these improved after the dose of PER was reduced. No discontinuation of PER was required due to side effects or intolerance.. In real-world settings, PER is well tolerated and effective in seizure control in pediatric and adolescent patients with DRE.

Topics: Adolescent; Anticonvulsants; Child; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Thailand; Treatment Outcome

The main aim of this study was to assess the efficacy, safety, and tolerability of adjunctive perampanel (PER) in the treatment of children and adolescents with epilepsy.. Pediatric patients who visited the pediatric epilepsy clinic of Henan Provincial People's Hospital between May 2020 and December 2021 were recruited. All participants were treated with PER as adjunctive therapy and were seen routinely (minimum: a baseline and 12-week visit). The efficacy and tolerability of adjunctive PER for the treatment of epilepsy were investigated.. One hundred and fourteen patients were enrolled, among whom 7 (6.1%) were lost to follow-up. At 12 weeks, the responder rate and the seizure-free rate were 56.1% (60/107) and 32.7% (35/107), respectively. The responder rate increased with the duration of PER administration and was significantly higher when PER was used as an early add-on (after ≤2 prior antiseizure medications (ASMs)) than a late add-on (after >2 prior ASMs). However, there was no significant difference in the treatment efficacy of adjunctive PER in patients with different epilepsy etiologies or types. Adverse events, including irritability, dizziness, somnolence, ataxic gait, weight gain, and tinnitus, were reported in thirty-two patients (29.9%).. In a routine clinical setting of pediatric patients with epilepsy, good effectiveness and tolerability of adjunctive PER were demonstrated. Notably, patients initiating PER as an early add-on showed a better seizure outcome than those initiating PER as a late add-on.

Topics: Adolescent; Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Humans; Pyridones; Retrospective Studies; Treatment Outcome

Migraine is a common comorbidity in patients with epilepsy. Considering the proven associations and the common pathophysiological features linking epilepsy and migraine, some anti-seizure medications (ASMs) have been considered as a treatment for both disorders. This study aimed at assessing both the effectiveness of perampanel (PER) on epileptic seizures and migraine attacks in patients with epilepsy and comorbid migraine, as well as the reduction in the monthly mean rate usage of rescue migraine medications.. This observational, multi-centre study included adult patients with epilepsy and comorbid migraine who started PER to better control epileptic seizures and who were followed up for 12 months.. Thirty-one patients were included (mean age 40.13 ± 13.13 years; 67.0% female). At the 12-month follow-up visit, 27 patients were continuing PER concomitantly with 1 (45.2%) or 2 ASMs (54.8%). A significant reduction in epileptic seizures, migraine attacks, and the monthly use of rescue migraine medications between baseline and both 6- and 12-month follow-up visits was documented.. PER demonstrated good effectiveness in reducing both epileptic seizures and migraine attacks in patients with comorbid epilepsy and migraine. Future studies with possibly larger samples are needed to evaluate the efficacy of PER in migraine other than epilepsy.

Topics: Adult; Anticonvulsants; Comorbidity; Epilepsy; Female; Humans; Male; Middle Aged; Migraine Disorders; Nitriles; Pyridones

The aim of this study was to evaluate the risk of hospitalization and emergency department admission following initiation of perampanel treatment in patients with epilepsy.. This study is a retrospective longitudinal cohort study (Optum® Clinformatics® Datamart). Patients 4 to 11 years of age with a diagnosis of partial onset seizures or ≥12 years of age with primary generalized tonic-clonic seizures who had ≥1 perampanel prescription between 1/1/2014 and 3/31/2018 were eligible for the study. Additionally, patients were required to have 12-months of continuous enrollment before (pre-) and after (post-) the date of the first perampanel prescription (index-date). One-year relative-risks of all-cause and epilepsy-related hospitalizations and emergency department (ED) visits were estimated following initiation of perampanel treatment. Outcomes were also evaluated among a subsets of patients who were adherent to perampanel treatment, defined as a Medication Possession Ratio (MPR) ≥80%.. A total of 320 patients were included in the study, mean age 38.2 ± 19 years, 56.6% female. In the overall population, the relative risks of hospitalizations or ED visits after perampanel initiation were not significantly different. Among the 145 patients who had an MPR ≥80%, initiation of perampanel treatment resulted in a significantly lower risk of epilepsy-related hospitalization (relative risk [RR] = 0.68, confidence interval [CI] [0.47, 0.98]), all-cause ED visits (RR = 0.80, CI [0.66, 0.98]), and epilepsy-related ED visits (RR = 0.74, CI [0.57, 0.95]) in the follow-up period.. Adherence to perampanel treatment was associated with significant reductions in one-year hospitalizations and ED visit risk in real world settings.

Topics: Adult; Anticonvulsants; Child; Epilepsy; Female; Hospitalization; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome; Young Adult

Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug.. A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved.. Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.

Topics: Activities of Daily Living; Adult; Anticonvulsants; Basal Ganglia; Epilepsy; Humans; Leigh Disease; Magnetic Resonance Imaging; Male; Mutation; Nitriles; Pyridones; Seizures; Treatment Outcome

Quantitative EEG (qEEG) is an established technique used as objective measure for evaluating the effect of antiseizure medications (ASMs) on EEG background activity and monitoring cognitive effects of ASMs. Perampanel (PER) has been associated with relatively more tolerable cognitive effects in patients with epilepsy. The primary aim of the present study was to verify the effect of PER as first add-on ASM on qEEG in child and adult patients affected by epilepsy. The secondary aim of this study was to verify the effectiveness of the drug as first add-on treatment in both child and adult patients with epilepsy.. We collected data from 17 adults and 10 children treated with PER as first add-on treatment, who underwent qEEG analysis before starting PER and at 3-month follow-up under stable treatment.. PER resulted with significant effectiveness in reducing seizures in both children and adults. Considering qEEG analysis, we observed at follow-up the significant increase in beta1 and beta total bands both in children and adult patients. In particular, children showed the significant increase of beta band frequencies predominantly in the occipital regions, whereas adults showed a widespread increase of beta activity. Moreover, we documented in both child and adult patients the global reduction of delta bands activity.. This qEEG study documented the relative increase of cortical EEG fast activity in both children and adult patients affected by epilepsy and treated by PER. This result may suggest a potential less negative impact of PER on cognition in patients affected by epilepsy, other than demonstrating effectiveness of the drug when used as first add-on treatment in both children and adult patients.

Topics: Adult; Anticonvulsants; Child; Electroencephalography; Epilepsy; Humans; Nitriles; Pyridones; Seizures

Topics: Epilepsy; Humans; Leigh Disease; Nitriles; Pyridones; Seizures

Perampanel is the latest anti-seizure medication introduced in the Philippines in 2015. This was initially approved as an adjunctive treatment for focal seizures and those with secondary generalization among individuals 12 years old and above. By March 2020, it has been approved also for generalized seizures and in children 4 years and above. The general objective of this research is to describe the clinical experience of Filipino child neurologists on the use of perampanel in children.. This is a cross-sectional descriptive study that surveyed child neurologists with review of medical records of children who have received perampanel as either an adjunctive therapy or monotherapy for epilepsy.. There were 65 patients included in the study aged 1 to 18 years with a mean age of 10.0 ± 5.2 years and a median of 10 years. Follow-up duration were between 2 weeks to more than a year. Perampanel was started in 98.5% as an add-on treatment between 5 months and 18 years of age. The responder rate is 69.2% (45/65), seizure-free rate is 29.2% (19/65), seizure-aggravation rate is 9.2% (6/65), and perampanel retention rate is 83.1% (54/65). Treatment emergent adverse events were noted in 53.8% of the children with somnolence (20.0%), gait problems (12.3%), weight gain (10.8%) and dizziness (9.2%) as the most common events experienced. Dizziness was experienced significantly more among children 12 to 18 years of age.. Perampanel is seen to be effective and relatively safe to use among Filipino children.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Cross-Sectional Studies; Epilepsy; Female; Humans; Infant; Male; Neurologists; Nitriles; Philippines; Practice Patterns, Physicians'; Pyridones; Surveys and Questionnaires; Treatment Outcome

Antiepileptic drugs are well known for their effects on cognition and electrophysiologic changes. However, perampanel is yet to be evaluated for its effects on cognitive function and electroencephalography (EEG). The purpose of the present study was to identify the effect of perampanel on neuropsychological (NP) tests and quantitative EEG (QEEG) and their relationship with the level of the drug in blood. Seventeen patients with epilepsy were enrolled in the study. Electroencephalographic recordings were obtained, and NP tests were conducted before perampanel intake and 6 months after treatment. The relative frequency band power, peak alpha frequency, and NP test scores were compared before and after drug administration. The serum concentration of perampanel was correlated with the QEEG changes. Delayed recall of the Rey Complex Figure showed significant improvement (20.03 vs. 22.94; P = 0.004) following perampanel administration. Other cognitive function tests showed no significant differences before and after drug administration. Theta frequency band power increased in all brain regions (P = 0.001-0.01), and alpha frequency power decreased in all brain regions (P = 0.006-0.03). The theta/alpha ratio, which represents background EEG slowing, increased in all brain areas (P = 0.003-0.02). The peak frequency of the alpha rhythm decreased after perampanel intake (t = 2.45, P = 0.03). Difference of relative alpha power in the central region positively correlated with the blood level of perampanel (r = 0.53, P = 0.03). Perampanel induced electrophysiological slowing, but cognitive decline was not observed. Because the controls were not compared in the study, the results of cognitive function tests should be interpreted conservatively. Background EEG slowing correlated with the serum concentration of perampanel. Our results show the effect of perampanel on cognitive function and background EEG in adult patients with epilepsy.

Topics: Adult; Cognition; Electroencephalography; Epilepsy; Humans; Neuropsychological Tests; Nitriles; Pyridones

The aim of this study was to assess the usefulness of perampanel (PER), and to identify the relationship between behavioral impairments and electroencephalogram (EEG) findings in epilepsy patients with autism spectrum disorder (ASD).. Participants were ASD patients with epilepsy recruited between June 1, 2016 and June 30, 2018. Inclusion criteria were: seizures refractory to two appropriate antiseizure medications (ASMs); presence of neuropsychological impairments; and ≥12 months of monitoring. PER was administered once daily, starting at a dose of 2 mg/day, increased to 12 mg/day. Seizure/EEG responders were identified as participants showing a >50 % reduction in seizure/interictal epileptiform discharge (IED) frequency (indicated as complete disappearance and response). Behavioral responders were identified as participants with a ≥50 % reduction in scores of the Japanese manuals for the Aberrant Behavior Checklist (ABC-J).. Eleven (64.7 %) of 17 patients were considered to be both seizure and EEG responders. Five (45.5 %) of these 11 patients with seizure/EEG response were considered as behavioral responders. Mean ABC-J scores were significantly decreased at 12 months after PER administration (p = 0.0002). A correlation between decreased IED frequency and ABC-J score was evident in frontal IEDs, but not in non-frontal IEDs. Participants presenting with frontal IEDs showed a significantly higher correlation between seizures/EEG and behavioral improvements (p = 0.023). Moreover, 2 of 6 patients without seizure/EEG improvement were considered as behavioral responders. No patients discontinued PER.. The results from this study suggest the utility of PER treatment in reducing clinical seizures and IEDs for ASD patients with intractable epilepsy, at least in some patients. Moreover, the present results also indicate the usefulness of PER in improving neuropsychiatric impairments, including behavioral disturbances in ASD related to improvement of clinical seizures/frontal IEDs, but also unrelated to seizure/EEG improvement in at least some ASD patients.

Topics: Autism Spectrum Disorder; Electroencephalography; Epilepsy; Humans; Nitriles; Pyridones; Seizures

About 30% of people with epilepsy (PWE) are drug-resistant. Those with focal seizures may be suitable for epilepsy surgery. Those not amenable to resective surgery can be considered for vagus nerve stimulation (VNS). However, after operative procedures, around 50% of patients continue to experience seizures. A multi-center retrospective study assessing perampanel effectiveness and tolerability for PWE who have undergone surgical resection and/or VNS implantation was performed. The primary outcome was ≥50% reduction in seizure frequency while secondary outcomes included side effects (SEs), dose-related effectiveness, and toxicity. The median perampanel dose was 6 mg. Only one PWE became seizure free. A ≥50% decrease in seizure frequency was observed in 52.8% of the post-resection group and 16.9% of the VNS group (p < 0.001), while SEs were seen in 44.8% and 41.1%, respectively. Perampanel doses greater than 8 mg led to better response in both groups, especially in the post-VNS cohort. SEs were not dose-related and the safety profile was similar to previous observational studies. Perampanel can be beneficial in these two super-refractory epilepsy groups, particularly in PWE with seizures after surgical resection. Doses of more than 8 mg appear to be well tolerated and may be more effective than lower doses in PWE after surgical interventions.

Topics: Drug Resistant Epilepsy; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome; Vagus Nerve Stimulation

The present study evaluated whether patients with epilepsy who received both levetiracetam (LEV) and perampanel (PER) therapy showed side effects of irritability. The study also examined the relationship between patient characteristics and irritability when it occurred as a side effect.. We retrospectively examined medical records of 98 patients with epilepsy who were treated with both LEV and PER at the Department of Psychiatry in the Epilepsy Center of Nishiniigata Chuo National Hospital in Japan. We performed multiple regression analyses with the presence/absence of irritability due to LEV or PER as the dependent variables and clinical characteristics of the patients as independent variables.. LEV and PER caused irritability in 7 and 17 of 98 patients, respectively. LEV- and PER-related irritability did not occur in the same patients. A logistic multiple regression analysis revealed that EEG findings of temporal focal epileptic discharge were significantly associated with increased incidence of irritability due to LEV. LEV-related irritability decreased significantly with higher dosages of LEV. Another logistic multiple regression analysis revealed that a psychiatric comorbidity of irritability and EEG findings of nontemporal focal epileptic discharge were significantly associated with increased incidence of irritability due to PER.. LEV and PER cause irritability in different patient groups. Additionally, irritability as a side effect was present only at low dosages of LEV, but PER tended to cause irritability even at high dosages.

Topics: Anticonvulsants; Epilepsy; Humans; Japan; Levetiracetam; Nitriles; Piracetam; Pyridones; Retrospective Studies

Topics: Cognition; Electroencephalography; Epilepsy; Humans; Nitriles; Pyridones

With an elimination half-life of 105 hours, perampanel (PER) allows a once-daily dosing regimen. In pivotal trials, when PER was tapered, it was therefore usually discontinued abruptly. Thus, in our hospital we have always practiced abrupt cessation. In this case series, we investigated how long PER serum concentrations still remain measurable after abrupt discontinuation of PER and whether withdrawal symptoms, such as an increase in seizures or status epilepticus, occur. PER serum levels and the clinical course of 15 adult in-patients were monitored for three weeks based on a retrospective study design following abrupt discontinuation of PER. After one week, PER was still detected in 13 of 15 patients, after two weeks in 10, and after three weeks in three. Neither a severe increase in seizure frequency nor status epilepticus occurred. However, modifications of the concomitant antiseizure drugs were necessary. The abrupt discontinuation of PER leads to a slow decrease in plasma concentration, thus resembling self-evident gradual discontinuation of PER. In some cases, PER may still be measurable and thus clinically active even weeks after its discontinuation. Efficacy and safety of other antiseizure drugs can be estimated appropriately only thereafter.

Topics: Adult; Anticonvulsants; Drug Administration Schedule; Drug Tapering; Epilepsies, Partial; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies

The purpose of the study was to investigate the positive and negative effects of perampanel (PER) treatment on the psychiatric and behavioral symptoms in patients with epilepsy and to evaluate factors associated with the psychiatric and behavioral changes caused by PER.. We retrospectively examined medical records of patients with epilepsy treated with PER in the Department of Psychiatry, Epilepsy Center, Nishiniigata Chuo National Hospital. Multiple regression analyses were performed with the psychiatric and behavioral prognoses as dependent variables and clinical characteristics of the patients as independent variables.. Thirty-two of 135 patients (23.7%) had psychiatric and behavioral deterioration after the initiation of PER, whereas 22 patients (16.3%) showed improvement in psychiatric and behavioral symptoms after PER administration. Etiology of structural abnormalities, concomitant use of nitrazepam, and comorbidities of irritability and depression were significantly associated with increasing incidence of psychiatric and behavioral deterioration. Concomitant use of carbamazepine was significantly associated with decreasing incidence of psychiatric and behavioral deterioration. Suppression of awareness-impaired seizures by PER, concomitant use of carbamazepine, and comorbidities of insomnia, anxiety, and amnesia were significantly associated with an increasing incidence of psychiatric and behavioral improvement. Improvements in psychiatric symptoms by PER were associated with a reduction in the use of psychotropic drugs. In particular, about 1/4 of benzodiazepines had been discontinued.. Perampanel therapy may aggravate or even ameliorate psychiatric and behavioral symptoms in patients with epilepsy. The psychiatric and behavioral prognoses after administration of PER vary depending on the type of psychiatric and behavioral comorbidities in patients with epilepsy. Psychiatric and behavioral symptoms may improve in patients with successful suppression of seizures by PER. Additionally, combination therapy consisting of PER and carbamazepine may be associated with good outcomes of psychiatric and behavioral symptoms in patients with epilepsy.

Topics: Adult; Anticonvulsants; Behavioral Symptoms; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

Topics: Cognition; Electroencephalography; Epilepsy; Humans; Nitriles; Pyridones

The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy.. Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy.. Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively.. These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.

Topics: Adult; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Middle Aged; Nitriles; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pyridones; Rabbits; Rats; Rats, Sprague-Dawley; Young Adult

Epilepsy is common in patients with brain tumors and frequently presents as the first clinical manifestation of an underlying tumor. Despite a number of available antiepileptic drugs (AED), brain tumor related epilepsy (BTRE) may still be difficult to control. Recently, the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptor antagonist perampanel (PER) is increasingly acknowledged as an attractive novel add-on AED for seizure control in BTRE. We present a single institutional experience reporting five individual cases with refractory BTRE treated with PER. In two of these five brain tumor patients, worsening of seizure control was caused by SMART-syndrome (stroke-like migraine attacks after radiation therapy). Efficacy of PER was assessed by the responder rate and by evaluating overall changes in seizure frequency before and during PER treatment. In our case series, a reduction in seizure frequency was observed in four out of five patients and the responder rate was 40%. In addition, both cases with symptomatic epilepsy associated with SMART-syndrome were successfully treated with PER. This case series supports the growing evidence that PER may become a promising add-on AED for the treatment of refractory BTRE as well as for seizure control in SMART-syndrome.

Topics: Anticonvulsants; Brain Neoplasms; Epilepsy; Humans; Nitriles; Pyridones; Treatment Outcome

Combination regimens of antiepileptic drugs (AEDs) with various mechanisms of action (MOA) are commonly used in patients with refractory epilepsy. However, outcomes related to combination AEDs with novel MOA, such as perampanel (PER), are not well described. This study compared healthcare resource utilization (HRU) among recipients of PER-based combinations versus recipients of other non-PER-based combinations.. This retrospective study used claims data from the Symphony Health's IDV® (Integrated Dataverse) database (August 2012 to July 2018). Patients were aged ≥12 years with epilepsy or non-febrile convulsions, were treated with AED combinations, and had ≥12 and ≥6 months pre- and post-index date, respectively (date of initiation of the second AED in the combination). AEDs were categorized based on MOA: selective non-competitive antagonist of AMPA receptors (i.e., PER), sodium channel blocker (SC), synaptic vesicle protein 2A binding (SV2), and gamma-aminobutyric acid analog (G). Patients were then classified into MOA-based cohorts: PER + SC, PER + SV2, PER + G, SC + SC, SC + SV2, SC + G, SV2 + G, and G + G. HRU outcomes were evaluated during follow-up and compared between PER-based cohorts and non-PER-based cohorts.. On average, patients in the PER + SC (N = 3,592), PER + SV2 (N = 2,200), and PER + G (N = 1,313) cohorts were younger and had a lower Quan-Charlson comorbidity index than those in non-PER-based cohorts. PER + SC and PER + SV2 users had significantly fewer all-cause hospitalizations than non-PER-based users (adjusted RR range: 0.66-0.89, all P < 0.05), while PER + G recipients had fewer all-cause hospitalizations than recipients of SV2 + G and G + G (adjusted RR range: 0.92-0.94). Similar trends were observed for epilepsy-related hospitalizations. Across all comparisons, PER-based combinations were associated with significantly lower rates of all-cause clinic/office/outpatient visits relative to non-PER-based combinations (adjusted RR range: 0.69-0.86, all P < 0.05).. Results showed that patients treated with PER-based combinations had fewer all-cause and epilepsy-related hospitalizations, and fewer all-cause clinic/office/outpatient visits compared with patients treated with most other non-PER-based combinations.

Topics: Aged; Anticonvulsants; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; United States

This study aimed to evaluate the efficacy and tolerability of perampanel (PER) as adjunctive therapy in patients with pharmacoresistant sleep-related hypermotor epilepsy (SHE). Patients diagnosed with SHE who received PER treatment between 2016 and 2019 were included, and their data were reviewed retrospectively. Diagnosis was based on reports of patients or family members witnessing the events and clinical characteristics of seizures captured by video or during video-electroencephalography monitoring. Among 36 SHE patients, 20 with pharmacoresistant SHE (six female; mean age: 34.1 ± 9.0 years) who received PER as adjunctive therapy were included in this study. Fourteen out of the 20 patients received PER with mean length of PER exposure of 24.6 ± 15.7 months: 10 of them were responders and four non-responders. The remaining six patients discontinued PER for adverse events (n = 5) and patient choice (n = 1). Among the 10 responders, six (60%) reported seizure-free periods lasting ≥6 months. The most common PER-associated adverse event was dizziness (25%) followed by malaise (10%). Clinical experience with these patients demonstrated that PER might be considered as an add-on anti-seizure medication for patients with highly pharmacoresistant SHE.

Topics: Adult; Anticonvulsants; Epilepsy; Female; Humans; Male; Nitriles; Pyridones; Receptors, AMPA; Retrospective Studies; Sleep; Treatment Outcome

Perampanel is one of the most recently approved antiseizure medications. The aim of the present study was to assess clinical efficacy and tolerability, in combination with pharmacokinetic variability, of perampanel treatment in patients at a tertiary referral center for epilepsy.. We performed a retrospective observational study of patients given perampanel as adjunctive treatment in the period January 2013 - February 2019 at the National Center for Epilepsy at Oslo University Hospital, Norway.. Clinical data were available for 175 mainly adult patients with drug-resistant epilepsy with mean treatment duration of 16.1 months. We found that 23% (40 patients) were responders (i.e., achieving more than 50% reduction in seizure frequency), four of whom became seizure free, 29% (51 patients) experienced a modest effect, whereas for 29% (50 patients) perampanel had no seizure-reducing effect. A paradoxical effect, with seizure aggravation, was reported in 9% (15 patients). The responder rate was significantly higher in those with slow vs. fast dosage titration. Logistic regression analysis showed better efficacy among those with generalized vs. those with focal epilepsy. Adverse effects were reported by 135 patients (77%), ranging from mild (34%), to moderate (41%) and severe (2%). In 55 patients (41%), these adverse effects resulted in discontinuation of treatment with perampanel. The most frequent adverse effects were psychiatric symptoms (34%), dizziness (31%), and sleepiness (26%). Of the 31 patients for whom serum concentration measurements were available, the mean daily perampanel dose was 6.3 mg (SD 3.0), with a mean serum concentration at steady state of 1.03 μmol/L (range: 0.15-3.59 μmol/L). There were pronounced differences between patients, as demonstrated by a 12-fold variability in the range of concentration/dose (C/D)-ratios (0.06 to 0.69 μmol/L/mg), where enzyme inducers contributed.. Our results demonstrate that perampanel had a modest seizure-reducing effect in this very treatment-resistant patient group. Predictors of treatment success were generalized epilepsy and slow dosage titration. In patients without a history of psychiatric problems, clinicians could consider increasing dose of perampanel beyond 6 mg daily, taking co-medication and serum concentrations into account.

Topics: Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Norway; Pharmaceutical Preparations; Pyridones; Treatment Outcome

Clinical data regarding use of newer antiseizure medications (ASMs) in an older population are limited. In randomized-controlled, placebo-controlled trials, older patients are under-represented, and protocols deviate markedly from routine clinical practice, limiting the external validity of results. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Perampanel is a third-generation ASM and the first and only non-competitive alfa-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist.. The aim of this study was to assess the effectiveness and tolerability of adjunctive perampanel over a 1-year period in a population of older patients with epilepsy treated in a real-world setting.. Older (≥ 65 years of age) patients prescribed add-on perampanel at 12 Italian epilepsy centers were retrospectively identified. Seizure occurrence, adverse events (AEs), and drug withdrawal were analyzed. Effectiveness outcomes included the rates of seizure response (≥ 50% reduction in baseline monthly seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes were the rate of treatment discontinuation due to AEs and the incidence of AEs.. A total of 92 patients with a median age of 69 (range 65-88) years were included. The median daily dose of perampanel at 12 months was 6 mg (interquartile range 4-6 mg). At 12 months, 53 (57.6%) patients were seizure responders, and 22 (23.9%) patients were seizure free. Twenty (21.7%) patients discontinued perampanel; the reasons for treatment withdrawal were insufficient efficacy (n = 6/20; 30.0%), AEs (n = 12/20; 60.0%), and a combination of both (n = 2/20; 10%). The most common AEs included irritability (8.7%), somnolence (4.3%), and dizziness/vertigo (4.3%). The rate of behavioral and psychiatric AEs was higher in patients with history of psychiatric comorbidities (p = 0.044). There were no differences in the occurrence of behavioral and psychiatric AEs according to the concomitant use of levetiracetam (p = 0.776) and history of cognitive decline (p = 0.332).. Adjunctive perampanel was associated with improvement in seizure control and good tolerability in a real-life setting and can represent a viable therapeutic option in older patients with epilepsy.

Topics: Aged; Aged, 80 and over; Anticonvulsants; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

The main of the present study was to assess the effectiveness and tolerability of perampanel (PER) in association with 1 or 2 concomitant antiseizure medications (ASMs) in patients with epilepsy throughout a follow-up period of 24 months or longer in a real-world setting.. This retrospective, observational, multi-center study collected data from both underage (<18 years old) and adult patients who had started PER in association with 1 or 2 ASMs. Only patients who had started PER and were followed up for at least 24 months were included. Response to treatment was analyzed at the 24-, 36-, and 48-month visits by considering the last visit undergone by patients. Subgroup analyses were performed according to age, gender, and epilepsy type and patients were categorized following PER treatment in concomitance with 1 or 2 ASMs to evaluate the factors affecting the achievement of seizure freedom (SF) at the 24-month FU.. Ninety-four patients were included (mean age 36.89 years; 51.1% female). At the 24-month follow-up visit, 90 (95.74%) patients were still receiving PER concomitantly with 1 or 2 ASMs. The mean PER dose was 6.02 mg/day and SF was achieved by 33 (35.1%) patients. A significantly higher SF rate was found in patients who had started PER with only 1 ASM when compared to those who had started PER with 2 concomitant ASMs. Effectiveness was maintained also in the subgroups of patients with a 36- or 48-month follow-up visit. Adult patients had a higher final daily dosage of PER than underage patients. Logistic regression found that the lowest number of previously failed ASMs was associated with a higher SF rate (p = 0.036).. Perampanel demonstrated a good effectiveness in association with 1 or 2 ASMs in both pediatric and adult patients, without having to use a high dose of the drug. The possibility to present SF was higher when PER was added early. Finally, the maintenance of effectiveness was observed also in the subgroups of patients with a follow-up of 36 and 48 months.

Topics: Adolescent; Adult; Anticonvulsants; Child; Epilepsy; Female; Follow-Up Studies; Humans; Male; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

(1) To evaluate risk of hospitalization following initiation of perampanel (pre- and post-analysis) and (2) to compare hospitalization rates following initiation of perampanel vs lacosamide.. Patients were identified from Symphony Health's Patient Integrated Database if they had a prescription for perampanel (July 1, 2014-June 30, 2016). Patients 4-11 years of age with any partial-onset seizure (POS) or ≥12 years of age with any POS or primary generalized tonic-clonic seizure (GTCS) (pre-post); or ≥12 years of age (perampanel vs lacosamide). The first fill of perampanel ("index date") marked the start of the analysis period. Patients had ≥1 additional fill for perampanel and ≥2 diagnoses for epilepsy or nonfebrile convulsion diagnosis during pre-index (based on ICD-9/ICD-10 codes). Patients were matched using a 1:1 propensity scoring method for the perampanel vs lacosamide analysis. Primary outcome was hospitalization during the one year following medication initiation.. Pre- and post-perampanel: N = 1771 (mean age 34 years, 55% female). One-year all-cause hospitalization risk ratio was 0.76 (P < .05) and 36.2% with hospitalization during the pre-period vs 29.5% in the follow-up. One-year epilepsy-related inpatient hospitalization risk ratio was 0.72 (P < .05) and 30.8% with hospitalization during the pre-period vs 23.9% during follow-up. In the perampanel and lacosamide cohorts, N = 1717 per cohort after matching, most baseline demographics were balanced. A higher percentage of subjects were prescribed ≥3 anti-seizure medications for perampanel vs lacosamide (60.5% vs 57.7%, P < .001). The perampanel cohort had a 9.6% reduction in all-cause hospitalizations vs 5.8% for the lacosamide cohort (P < .05). Epilepsy-related hospitalizations decreased from the pre-index rate by 9.9% for perampanel and 8.3% for lacosamide (P < .05). Among those with baseline hospitalizations, perampanel was associated with a 59.9% reduction in all-cause hospitalizations vs 48.6% for lacosamide (P < .05), and for epilepsy-related hospitalizations, a reduction of 65.0% vs 58.9%, respectively (P < .05).. Perampanel was associated with a significant reduction in one-year hospitalization risk.

Topics: Adult; Anticonvulsants; Child; Epilepsy; Female; Hospitalization; Humans; Male; Nitriles; Pyridones

Perampanel (PER) has been shown to be effective as an adjunctive therapy for controlling refractory focal-onset seizures (FOS). However, the information as early add-on for the treatment of FOS in the clinical practice is still scarce and must be further assessed.. An observational prospective study was conducted to evaluate the effectiveness of early add-on PER, assessed as 50% responders (seizure frequency reduced by at least 50% during the last 3 months as compared with baseline) rate at 6 and 12 months, in patients with FOS in the routine clinical practice of Spain.. One hundred and thirteen patients (mean age: 40.3 years, 51.3% male) with FOS received PER as early add-on (1st add-on: 37.2% and 2nd: 62.8%) for a mean exposure of 11 months (mean PER dose: 6.3 mg/day at month 12). At 6 months, 50.4% and 20.4% of the patients were responders and seizure-free (respectively) relative to baseline (3 months prior to PER initiation), and at 12 months, 68.1% and 26.5% of the patients were responders and seizure-free (respectively), relative to baseline (3 months prior to PER initiation). The retention rate at 6 and 12 months was 83.2% and 80.5%, respectively. The percentage of seizure-free patients at 12 months was significantly (p = 0.033) higher when PER was added as first vs. second add-on. The number of concomitant antiepileptic drugs (AEDs) was significantly reduced from baseline to 6 and 12 months (p = 0.001). Treatment was simplified in 23.9% of patients at the end of the observation period. Drug-related adverse events (AEs), most mild or moderate, were reported in 30.1% of patients, with irritability (8%) and dizziness (7.1%) as the most frequent ones.. This is the first observational, prospective study to evaluate efficacy and safety of early adjunctive treatment with PER in patients with focal epilepsy at 12 months. Perampanel demonstrated a good efficacy and safety profile when used at a median dose of 6 mg/day, regardless of the combination with other AEDs. Adverse events were mild or moderate, with dizziness being the most frequent one.

Topics: Adult; Anticonvulsants; Dizziness; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Seizures; Spain; Treatment Outcome; Young Adult

Loss-of-function SYNGAP1 mutations cause a neurodevelopmental disorder characterized by intellectual disability and epilepsy. SYNGAP1 is a Ras GTPase-activating protein that underlies the formation and experience-dependent regulation of postsynaptic densities. The mechanisms that contribute to this proposed monogenic cause of intellectual disability and epilepsy remain unresolved.. A progressive worsening of the epilepsy with emergence of multiple seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1. Acute dosing with perampanel significantly rescued behavioral state-dependent cortical gamma homeostasis, identifying a novel mechanism implicating Ca

Topics: Animals; Epilepsy; Interneurons; Mice; Nitriles; Parvalbumins; Pyridones; ras GTPase-Activating Proteins; Up-Regulation

Possible loss of efficacy and potential interactions between antiepileptic drugs (AEDs) and chemotherapy could complicate the management of patients with brain tumor-related epilepsy (BTRE) that may expose patients to an increased risk of adverse events. Perampanel (PER) is a highly selective, noncompetitive, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptor antagonist. This study evaluates the effectiveness, QoL, cognition, and mood of PER in add-on therapy in BTRE patients.. Observational pilot study on the effectiveness of PER as add-on therapy in BTRE patients with uncontrolled seizures with a 6-month follow-up.. We recruited 26 BTRE patients. During the follow-up, 16 underwent chemotherapy and 11 radiotherapy; 11 had disease progression. Five patients dropped out. Mean daily PER dosage was 6.6 mg in the 21 patients who completed the follow-up and 6.4 mg in the ITT population. The mean number of seizures/month decreased from 10.8 ± 15.03 at baseline to 1.7 ± 4.34 in the 21 patients who reached the final follow-up. Responder rate was 88.4%: Eight patients were seizure-free, 15 had ≥50% seizure reduction, and 3 remained stable. Four patients (15.4%) reported AEs: 2 required PER dose reduction, and 2 dropped out. Neuropsychological, mood, and QoL questionnaires were not statistically different compared to baseline. There were no significant differences in seizure control in patients with/without IDH1 mutation and with/without MGMT methylation.. Perampanel proved to be effective on seizure control in BRTE patients and to be well tolerated without negative effects on cognition and QoL. Perampanel could be a valid therapeutic option in BTRE.

Topics: Anticonvulsants; Brain Neoplasms; Epilepsy; Humans; Nitriles; Pilot Projects; Pyridones; Quality of Life; Treatment Outcome

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) helps optimize drug management for patients with epilepsy. Salivary testing is both noninvasive and easy, and has several other advantages. Due to technical advances, salivary TDM has become feasible for several drugs, including AEDs, and its value has been investigated. Until recently, saliva TDM of perampanel (PER) had not been reported. The purpose of our study was to confirm whether saliva is a biological substitute for plasma in PER TDM.. Adult patients diagnosed with epilepsy who received PER from August 2018 to March 2019 at Seoul National University Hospital were enrolled. Total and free PER were measured in simultaneously obtained plasma and saliva samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatographic (HPLC). We examined the correlations between saliva and plasma PER concentrations and whether the use of concomitant medications classified as cytochrome P450 (CYP)3A4 inducers affected the correlations.. Thirty patients were enrolled, aged 16 to 60; 10 (33%) were women. Patients received 2 to 12 mg (mean, 6 mg) of PER. The average total and free concentrations of PER were 343.02 (46.6-818.0) and 1.53 (0.51-2.92) ng/mL in plasma and 9.74 (2.21-33.0) and 2.83 (1.01-6.8) ng/mL in saliva, respectively. A linear relationship was observed between the total PER concentrations in saliva and the total and free PER concentrations in plasma (both P < .001; r = .678 and r = .619, respectively). The change in the PER concentration caused by the CYP3A4 inducer did not affect the correlation between saliva and plasma concentrations (all P < .001).. The PER concentration in saliva was correlated with that in plasma. This correlation was not affected by CYP3A4 inducers. Our results demonstrate for the first time that PER is measurable in saliva and suggest the potential for the clinical application of the saliva PER TDM matrix.

Topics: Adolescent; Adult; Anticonvulsants; Chromatography, Liquid; Drug Monitoring; Epilepsy; Female; Humans; Male; Mass Spectrometry; Middle Aged; Nitriles; Pyridones; Saliva; Young Adult

Epilepsy prevalence is over 20% for those with ID. It is difficult to diagnose and treat and more likely to be treatment resistant. The evidence informing prescribing is sparse, particularly for new drugs such as perampanel (PMP).. This study seeks to strengthen the research evidence regarding PMP for people with ID by pooling information from two isolated and separately conducted studies: the UK-based Epilepsy Database Register (Ep-ID) and the data from the Kempenhaeghe clinic in the Netherlands.. A single data set of comparable data was created and analysed under agreement and supervision of a UK statistician.. Seizure reduction within twelve months was evident in 62% of Dutch and 47% of UK patients. Retention rates were higher for those in the UK (P = .01) and for patients with moderate to profound ID, whilst side effects were more prominent in the Dutch cohort.. Comparable rates of seizure reduction are in line with estimates for non-ID patients, adding to the evidence suggesting that PMP has a similar impact on those with ID. Taking a European perspective and sharing data across centres can help strengthen the evidence for prescribing antiepileptic drugs in the ID population.

Topics: Adolescent; Adult; Anticonvulsants; Cohort Studies; Databases, Factual; Epilepsy; Female; Humans; Intellectual Disability; Male; Middle Aged; Netherlands; Nitriles; Pyridones; Registries; Seizures; Treatment Outcome; United Kingdom; Young Adult

The amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is increasingly recognized as a therapeutic target in drug-refractory pediatric epilepsy. Perampanel (PER) is a non-competitive AMPAR antagonist, and pre-clinical studies have shown the AMPAR-mediated anticonvulsant effects of decanoic acid (DEC), a major medium-chain fatty acid provided in the medium-chain triglyceride ketogenic diet.. Using brain tissue resected from children with intractable epilepsy, we recorded the effects of PER and DEC in vitro.. We found resected pediatric epilepsy tissue exhibits spontaneous epileptic activity in vitro, and showed that DEC and PER inhibit this epileptiform activity in local field potential recordings as well as excitatory synaptic transmission.. This study confirms AMPAR antagonists inhibit epileptiform discharges in brain tissue resected in a wide range of pediatric epilepsies.

Topics: Adolescent; Anticonvulsants; Brain; Child; Child, Preschool; Decanoic Acids; Drug Resistant Epilepsy; Epilepsy; Female; Humans; Male; Nitriles; Patch-Clamp Techniques; Pyridones; Receptors, AMPA; Synaptic Potentials

We compared health service utilization and costs for patients with epilepsy before and after initiation of perampanel and compared with matched controls.. Patients were selected from the Clinical Practice Research Datalink (CPRD). Patients initiating perampanel were matched to controls initiating an alternate add-on therapy for the same underlying epilepsy subtype. First prescription defined index date. Primary and secondary care contacts and associated costs were aggregated in the 12 months before and after index date. Secondary care contacts were available for a subset (~60%) of patients.. Three hundred and forty-three patients treated with perampanel were identified. One hundred and eighty-three (53.4%) were male, mean age was 39.1 (sd: 16.0). Mean epilepsy duration was 21.1 (standard deviation (sd): 13.3) years. Two hundred and eighty-seven (83.7%) were matched to controls. Inpatient admissions with a primary diagnosis of epilepsy (0.5 versus 0.2 per patient-year (ppy), p = 0.002) and neurology specific outpatient appointments (3.2 versus 2.9 ppy, p = 0.041) were significantly reduced following initiation with perampanel. Total costs attributable to epilepsy (£1889 to 1477 ppy) and overall secondary costs (£2593 to £2102) were also significantly reduced. There was no significant difference in primary care, outpatient, or general inpatient admissions. Compared with controls, there was a significant reduction in primary epilepsy admissions (incidence rate ratio (IRR): 0.423; 95% Confidence intervals (CI): 0.198-0.835) but a significant increase in outpatient appointments (1.306; 95% CI: 1.154-1.478) and accident and emergency contacts (1.603; 95% CI: 1.081-2.390) for patients treated with perampanel.. Treatment with perampanel is associated with reduced epilepsy-related inpatient admissions and accident and emergency contacts.

Topics: Adult; Anticonvulsants; Epilepsy; Female; Health Care Costs; Health Services; Hospitalization; Humans; Male; Middle Aged; Nitriles; Patient Acceptance of Health Care; Pyridones; Retrospective Studies

The purpose of this study was to determine the efficacy of perampanel (PER) on secondary bilateral synchrony (SBS) and behavioral problems in adolescents with epilepsy who showed insufficient response to levetiracetam (LEV).. The primary criterion for patient selection was the presence of SBS. The criteria such as age between 12 and 18 years, seizures refractory to antiseizure medications including LEV, at least four seizures a month, neuropsychological impairments, and at least 12 months of follow-up also had to be fulfilled. Patients were given PER at an initial dose of 2 mg/day, followed by increments of +2 mg/day every 2 weeks. Concomitant medications remained unchanged during evaluation period. Responders for electroencephalogram (EEG) and seizures were identified as showing a ≥50 % reduction from the baseline SBS on EEG and seizure frequency, respectively. Neuropsychological impairments as per the Japanese manuals for the Aberrant Behavior Checklist (ABC-J) were evaluated before and after PER administration.. Eight of 14 patients were considered responders for seizures. Among these 8 responders, 6 patients were considered responders for EEG and behavioral problems. Mean ABC-J scores in both EEG non-responders and responders were decreased significantly at 12 months (p < 0.05 and p < 0.05, respectively). ABC-J scores were significantly lower in EEG responders than in EEG non-responders at 12 months (p < 0.01). Moreover, among patients with decreased ABC-J scores, the degree of decrease was larger in EEG responders than in EEG non-responders (p < 0.01).. PER may be useful in reducing SBS on EEG, seizure frequency, and behavioral problems.

Topics: Adolescent; Anticonvulsants; Epilepsy; Humans; Infant; Levetiracetam; Nitriles; Piracetam; Problem Behavior; Pyridones; Treatment Outcome

Quantifying epileptiform discharges before and after the initiation of treatment can be useful for evaluating the efficacy of antiepileptic drugs in generalized epilepsy. The aim of this study was to determine if the selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist perampanel alters the electroencephalographic signals in patients with drug resistant generalized seizures (primary or secondary). We also assessed the clinical efficacy, safety and tolerability of perampanel as an adjunctive treatment for patients with refractory generalized seizures after 3, 6 and 12 months of treatment to determine if there is an electro-clinical correlation. We carried out a 1-year retrospective, unicentric, observational, descriptive and non-interventional study to analyze changes in epileptiform discharges, seizure frequency and adverse effects in patients with generalized seizures taking perampanel as an add-on treatment. Perampanel significantly reduced the total number, total duration, maximal duration and average duration of epileptiform discharges in patients with primary generalized epilepsy (n = 44). In patients with focal onset epilepsy and secondary generalized seizures (n = 8) significant decreases in the maximal duration and average duration of epileptiform discharges were found. These findings correlate with the significant decrease in seizure frequency and clinical improvement observed after taking perampanel as an adjunctive therapy for 3, 6 and 12 months. To our knowledge, this is the first study to show that perampanel reduces epileptiform activity, and that this effect correlates with patients' clinical improvement. Analysing patients' electroencephalographic activity in response to perampanel could be useful for assessing the drug's efficacy and optimising adjunctive treatments.

Topics: Adult; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Female; Humans; Male; Nitriles; Pyridones; Seizures; Treatment Outcome

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.

Topics: Animals; Benzodiazepines; Chronic Disease; Down-Regulation; Epilepsy; Hippocampus; Male; Models, Biological; NF-kappa B; Nitriles; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyridones; Rats, Sprague-Dawley; Receptors, AMPA; Up-Regulation

Perampanel (PER) is a new-generation antiepileptic drug that has an occasional but significant shortcoming, psychiatric adverse effects (PAEs). Recently, antiepileptic drug-related adverse reactions, such as skin rash and even PAEs, have been discovered to be correlated with certain human leukocyte antigen (HLA) types. Thus, we aimed to analyze specific HLA alleles as risk factors for PER-PAEs. We prospectively enrolled 17 patients with epilepsy who were prescribed PER between May 2016 and Jul 2018 at Seoul National University Hospital and developed PAEs while taking PER. Their HLA types were analyzed compared to those of 19 patients in the PAE-tolerant group and the general Korean population. In silico docking was performed with two different computational programs, AutoDock Vina and SwissDock, to theoretically evaluate the binding affinity of PER in the grooves of the specific HLA alleles. The HLA-DQB1*06:01, DRB1*08:03, and B*54:01 alleles were significantly associated with the patients who developed PER-PAEs compared with the general Korean population (odds ratio [OR] 3.94, p = 0.008, OR 9.24, p = 0.037, and OR 3.25, p = 0.041, respectively). As a haplotype, the combination of the three alleles was significantly more frequent in the PER-PAE group than in both the PER-tolerant group and the general Korean population. DQB1*06:01 and B*54:01 also demonstrated higher docking scores with PER than other alleles. This is the first study to analyze the association of PER-PAEs with specific HLA genotypes. Our results suggest that an HLA-associated genetic predisposition and a possible immunological mechanism are involved in the occurrence of PER-PAEs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Genetic Predisposition to Disease; Genotype; HLA-DQ beta-Chains; Humans; Incidence; Male; Mental Disorders; Middle Aged; Nitriles; Pyridones; Republic of Korea; Young Adult

The potential benefit of perampanel for sleep disturbances is unknown. This study determined whether insomnia is less prevalent and less severe in patients with epilepsy (PWE) who take perampanel as an adjuvant.. This cross-sectional study was conducted in adults with epilepsy. Insomnia in patients treated or not treated with perampanel was diagnosed according to the criteria of the International Classification of Sleep Disorders, the third edition (ICSD-3) and the Insomnia Severity Index (ISI). Patients were also scored on the Epworth Sleepiness Scale (ESS), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7), and the groups were compared by stepwise linear or logistic regression analyses.. One hundred and twenty-six PWE were included in the study: 31 patients (24.6%) were taking perampanel. Insomnia was diagnosed in 15.9% and 20.6% of all patients according to the ICSD-3 and an ISI score of ≥15, respectively. Agreement between the two diagnostic methods was moderate (Cohen's kappa, 0.470). In a stepwise logistic regression model, insomnia diagnosed by either method was negatively associated with perampanel use (P<0.05) but positively correlated with depressive symptoms, anxiety, and duration of epilepsy. In a stepwise linear regression model, ISI scores correlated negatively with perampanel use (P=0.004) but positively with depressive symptoms (P<0.001) and anxiety (P=0.001).. Insomnia is less prevalent and less severe in PWE treated with perampanel independent of depressive symptoms, which will be helpful for treating PWE and comorbid sleep disturbances.

Topics: Adult; Cross-Sectional Studies; Depression; Epilepsy; Humans; Nitriles; Pyridones; Sleep Initiation and Maintenance Disorders

Perampanel (PER) has a unique pharmacological mechanism and marked efficacy in both focal and generalized epilepsy, but may cause adverse events similar to those of other antiepileptic drugs (AEDs). AEDs can affect multiple organ systems, as well as thyroid function, lipid profiles, and immunoglobulin levels; the low free T4 levels, hyperlipidemia, and low immunoglobulin levels can be caused by AEDs. While many studies have examined conventional AEDs, little is known about the long-term effects of PER on blood parameters.. We retrospectively reviewed the medical records of 18 pediatric patients with epilepsy who were treated with PER added to >1 other AED. Blood parameters (e.g., blood cell counts, biochemical and thyroid function, and immunoglobulin levels) were investigated at baseline and at 6 and 12 months after initiation of PER.. PER did not affect the blood counts, transaminase levels, lipid profile, or thyroid function at 12 months after initiation of PER. However, IgA levels significantly increased (p = 0.00319) without symptoms. IgM levels increased temporarily, but had returned to baseline by 12 months after initiation of PER.. IgA levels were elevated at 12 months after initiation of PER in pediatric patients with intractable epilepsy, although no symptoms were observed. PER did not affect other parameters, including lipid profile and thyroid function.

Topics: Adolescent; Anticonvulsants; Child; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsy; Epilepsy, Generalized; Female; Humans; Male; Nitriles; Pyridones

To investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD).. This multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy.. Of the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations.. PER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

Topics: Adult; Anticonvulsants; Epilepsies, Partial; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pharmaceutical Preparations; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Topics: Aggression; Depression; Epilepsy; Humans; Nitriles; Prospective Studies; Pyridones

Antiepileptic drug side effects are frequent, 42% of them corresponding to cosmetic changes. The most frequent effects are weight gain, gingival hyperplasia, and hair loss. Hair changes in texture or colour are rarely reported in the literature. We present a case of hair curling after the introduction of perampanel. A 13-year-old girl with genetically confirmed Pitt-Hopkins syndrome with uncontrolled seizures, while on treatment with levetiracetam and valproic acid, was started on perampanel, reaching seizure control. After a few weeks of the introduction of the new antiepileptic drug, she developed hair curling. Hair curling is a rare cosmetic side effect, reported mainly in patients under valproic acid treatment. Perampanel is a recently introduced pharmaceutical molecule with no prior reports of hair changes as a side effect. There is no clear explanation for this side effect, but it should be discussed with patients taking valproate whenever perampanel is added to the treatment.

Topics: Adolescent; Anticonvulsants; Epilepsy; Facies; Female; Hair; Humans; Hyperventilation; Intellectual Disability; Nitriles; Pyridones; Seizures; Treatment Outcome; Valproic Acid

Topics: Aggression; Depression; Epilepsy; Humans; Nitriles; Prospective Studies; Pyridones

Epilepsy occurs in 35-70% of patients with gliomas; glutamate plays a central role via AMPA-receptor activation, which is involved both in seizure activity and tumor growth. We conducted a retrospective study on brain tumor-related epilepsy patients (BTRE) treated with perampanel in add-on (PER) for 12 months, to evaluate efficacy and tollerability, according to real-life clinical practice.. Medical records of eleven patients (9 males, mean age 54 years) with glioma and epilepsy treated with PER in add-on, for inadequate seizure control or adverse events (AEs) from previous antiepileptic drugs (AEDs) therapy, were reviewed. Data collected included: tumor history, molecular factors, systemic therapy, type and number of seizures and concomitant AEDs, and AEs.. After 12 months of PER therapy, five patients were seizure-free, 4 had a seizure reduction ≥50% and the seizure frequency was unchanged in 2 patients. Responder rate was 81.8%. Two patients reported AEs; PER dose was reduced only in the one case. The final median dose of PER was 7.3 mg/day. We didn't find statistically significant differences in the comparison between mean values pre, mean values post and the average of decreasing number of seizures related to: histology, presence/absence of chemotherapy, radiotherapy, progression disease, KPS, IDH1, MGMT.. Despite the limitations due to small number of patients in a retrospective study, the high rate of responder and seizure-free patients suggest that PER could be a therapeutic option in BTRE. Prospective controlled studies are needed to confirm our data.

Topics: Anticonvulsants; Brain Neoplasms; Epilepsy; Female; Glioma; Humans; Male; Medical Records; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

Topics: Animals; Anticonvulsants; Drug Discovery; Epilepsy; Humans; Nitriles; Pyridones; Receptors, AMPA

Irritability has been described as a frequent adverse event in patients affected by epilepsy and treated with perampanel (PER), levetiracetam (LEV), and less frequently with valproic acid (VPA). Since the questionnaire for irritability (I-EPI) is a validated instrument to measure this psychiatric manifestation in patients affected by epilepsy, in this study we aimed at investigating the effect of PER as first add-on therapy on I-EPI. Moreover, we compared the effectiveness and I-EPI scores obtained at 12-month follow-up visits in patients treated by PER, LEV, or VPA in order to measure irritability as a consequence of these treatments.. We collected data from 17 patients treated by PER, 16 patients treated by LEV, and 16 patients under VPA treatment followed for 12 months.. We did not document significant changes of I-EPI questionnaire between baseline and follow-up in the PER group. As concerning the comparison of I-EPI among PER, LEV, and VPA groups, we documented lower global scores in PER than both LEV (P < 0.05) and VPA (P < 0.05) groups. Moreover, patients under PER treatment showed lower scores than LEV and VPA (P < 0.05) in I-EPI items measuring the gentle personality, anxiety of having epileptic seizures in front of others, and irritability in thinking that they can have an epileptic seizure.. This retrospective study described a stable and possibly lower degree of irritability in patients starting PER than LEV and VPA treatments, although we documented the comparable effectiveness of PER, LEV, and VPA as first add-on treatments in patients affected by uncontrolled epileptic seizures. However, the small sample of patients included in this study and the absence of I-EPI scores obtained at baseline visits in LEV and VPA groups require further investigations to confirm this preliminary evidence.

Topics: Adult; Anticonvulsants; Anxiety; Drug Therapy, Combination; Epilepsy; Female; Humans; Irritable Mood; Levetiracetam; Male; Nitriles; Personality; Preliminary Data; Pyridones; Retrospective Studies; Treatment Outcome; Valproic Acid

Epileptic seizures are frequent in patients with glioblastoma, and anticonvulsive treatment is often necessary. While clinical guidelines recommend all approved anticonvulsants, so far it is still unclear which of the available drugs is the best therapeutic option for treating glioma-associated seizures, also in view of possible anti-tumorigenic effects. In our study, we employed four patient-derived low-passage cell lines of glioblastoma and three cell lines of brain metastases, and challenged these cultures with four anticonvulsants with different mechanisms of action: levetiracetam, valproic acid, carbamazepine and perampanel. Cell proliferation was determined by bromodeoxyuridine incorporation. To further analyze the effects of perampanel, apoptosis induction was measured by caspase 3/7 activation. Glutamate release was quantified and glucose uptake was determined using 18F-fluorodeoxyglucose. Real-time polymerase chain reaction was employed to assess the expression of genes associated with glutamate release and uptake in brain tumor cells. Of the four anticonvulsants, only perampanel showed systematic inhibitory effects on cell proliferation, whereas all other anticonvulsants failed to inhibit glioma and metastasis cell growth in vitro. Metastasis cells were much more resistant to perampanel than glioblastoma cell lines. Glucose uptake was attenuated in all glioblastoma cells after perampanel exposure, whereas cell death via apoptosis was not induced. Extracellular glutamate levels were found to be significantly higher in glioblastoma cell lines as compared to metastasis cell lines, but could be reduced by perampanel exposure. Incubation with perampanel up-regulated glutamine synthetase expression in glioblastoma cells, whereas treatment with valproic acid and levetiracetam downregulated excitatory amino acid transporter-2 expression. Overall, our data suggest that perampanel acts as an anticonvulsive drug and additionally mediated anti-tumorigenic effects.

Topics: Anticonvulsants; Antineoplastic Agents; Apoptosis; Brain; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Epilepsy; Glioblastoma; Glutamic Acid; Humans; Nitriles; Pyridones; Receptors, AMPA; Seizures; Up-Regulation; Valproic Acid

Using specialized tools, we assessed patients receiving perampanel (PER) to investigate its effects on aggression and depression, as well as the impact of other concomitant antiepileptic drugs (AEDs) on those conditions.. Seventy-seven patients with epilepsy were initially enrolled, then examined at entry and 12 weeks later (endpoint). At both examinations, assessments were performed with the Buss Perry Aggression Questionnaire (BAQ) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Ultimately, 59 patients completed the study.. Total BAQ (p = 0.013) and NDDI-E (p = 0.000) scores at the endpoint were significantly increased in comparison with those at entry. Analysis with 4 subscales showed increases in both verbal and physical aggression, while multivariate analysis revealed that concomitant AED administration did not have a significant impact on the increase of BAQ or NDDI-E score. A dose-dependent effect of PER was confirmed in BAQ, but not NDDI-E results. PER was discontinued due to adverse psychiatric effects in 3.9% of the patients.. The present findings indicate that PER increases assessment scores indicative of aggression as well as depression. No additional aggression-augmenting effect was seen with concomitant AED administration.

Topics: Adolescent; Adult; Aged; Aggression; Anticonvulsants; Depression; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Treatment Outcome; Young Adult

To investigate the correlation between steady-state plasma concentrations of perampanel (PER) with efficacy and tolerability in adult patients with difficult-to-treat epilepsy.. PER plasma concentrations were assessed at steady-state conditions in 92 adult patients (57% female, 43% male, mean age 39,5 years, age range 20-73 years). All patients had been treated with PER at a stable dose for at least 3 weeks. Clinical efficacy was assessed on the day of measuring the plasma concentrations by a retrospective analysis of the seizure frequency and adverse effects.. The mean overall plasma concentration was 323,5 ng/ml (range 19 ng/ml - 2436 ng/ml). The corresponding mean dose was 7,5 mg (range 2 mg - 12 mg). PER dose and plasma concentration showed a close linear correlation. Plasma levels and doses varied widely concerning both efficacy and tolerability of PER. The differences between plasma levels of responders and non-responders were not statistically significant. Therefore a clinically useful general reference range could not be defined.. Our data do not indicate a reliable therapeutic range for PER plasma concentrations. Individual reference ranges varied widely. Therapeutic drug monitoring (TDM) may still be helpful in certain clinical situations.

Topics: Adult; Aged; Anticonvulsants; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome; Young Adult

Body weight (BW) gain may be induced by perampanel (PER) administration, similar to the well-known adverse effects of valproic acid and gabapentin. Intellectual disability (ID) and serum PER concentration may be risk factors of BW gain.. This study investigated how ID and serum PER concentration are associated with PER-induced BW gain.. Subjects were 76 patients with epilepsy (41 men, aged 16-70 years). All patients were divided by intelligence quotient (IQ) into no ID (IQ ≥ 70, n = 24), mild to moderate ID (70 > IQ ≥35, n = 31), and severe to profound ID (IQ < 35, n = 21) groups. BW was measured before and 2, 4, 6, and 12 months after initiation of PER treatment, and serum PER concentration at 12 months.. BW gains in the mild to moderate ID group at 4, 6, and 12 months were significantly (p <  0.05) higher than in the no ID and in the severe to profound ID groups. At 12 months, BW gain was associated with serum PER concentrations in the no ID (p =  0.034) and the mild to moderate ID (p =  0.001) groups but not in the severe to profound ID group. Multiple linear regression analysis found BW gain at 12 months was positively correlated with the mild to moderate ID group (β = 0.373, p =  0.002) and serum PER concentration (β = 0.241, p =  0.047).. The mild to moderate ID group gained more BW than the no ID group, suggesting that PER-induced food intake was greater due to weaker behavioral control in the mild to moderate ID group. The present study suggests a linear correlation between serum PER concentration and BW change.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Epilepsy; Female; Follow-Up Studies; Humans; Intellectual Disability; Male; Middle Aged; Nitriles; Pyridones; Regression Analysis; Time Factors; Weight Gain; Young Adult

Enzyme-inducing antiseizure drugs taken concomitantly with perampanel are known to influence perampanel serum concentrations. In this study, we examined perampanel dosage, serum concentrations, and the effect of concomitant enzyme-inducing antiseizure drugs in children for a 3-year period. A retrospective chart review determined patient age, weight, perampanel serum concentration and prescribed dose, and concomitant drugs. Of 87 patients included in the study, 41 were prescribed an enzyme-inducing antiseizure drug. Although perampanel dosage did not differ between patients prescribed/not prescribed enzyme-inducing antiseizure drugs, serum concentrations were significantly lower in patients taking enzyme-inducing antiseizure drugs (average serum concentration for the enzyme-inducing antiseizure drug group was still above the previously reported efficacious serum concentration of 70 ng/mL). Although perampanel serum concentrations are negatively influenced by enzyme-inducing antiseizure drugs in children, it is likely that efficacy would be improved in patients not concomitantly prescribed enzyme-inducing antiseizure drugs because pediatric perampanel dosing is similar to that reported in prior adult efficacy trials.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Infant; Male; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

To explore the retention rates and the efficacy and tolerability of perampanel (PER) by using monthly real life data for a period of 12 months.. Longitudinal outcomes of (PER) usage were assessed using actuarial statistics in an observational nonrandomised multicentre study of 181 people with epilepsy (PWE) refractory to first and second line drugs. Graded seizure outcomes, toxicity and the dose of PER were recorded for each month.. PWE were followed for a mean of 15.1 months. The total cumulative probability for retention on PER at 12 months was 61.7% and for ≥50% improvement was 38.2%. Most improvements in seizure control occurred soon after initiation of PER, 17% by one month, 32% by six months and 38% by twelve months, and mostly at low doses 53% on 2 mg and 90% up to 6 mg. Improvements, when they occurred, were sustained. The most common side effects were neuropsychiatric, occurring in 28%. The emergence of side effects did not appear to be dose related. Although people with intellectual disability (ID) were more likely to remain on PER they did not show improved seizure control and also reported more side effects. Patients treated with VNS and PER had a worse outcome.. Overall around a third of people showed a useful, response to PER therapy. The response to PER is noted usually early in the treatment and for the majority of the patients for doses up to 8 mg.

Topics: Actuarial Analysis; Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Female; Humans; Intellectual Disability; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Cognitive dysfunctions are frequent in patients with epilepsy. This comorbidity significantly alters their quality of life and plays an important role in their therapeutic management. Perampanel is a noncompetitive antagonist of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and is considered a new generation AED (antiepileptic drug) with limited impact on cognitive functions.The aims of this study were to evaluate the efficacy of perampanel as first add-on therapy and its impact on cognitive functions and quality of life in patients with epilepsy followed for 6 months at the Neurology Division of "A. Cardarelli" Hospital in Naples (Italy).

Topics: Adult; Anticonvulsants; Cognitive Dysfunction; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Quality of Life; Retrospective Studies; Treatment Outcome; Young Adult

Perampanel is approved for adjunctive treatment of focal seizures, with or without secondarily generalised seizures, and for primary generalised tonic-clonic seizures in people with epilepsy aged ≥12 years. Perampanel was recently approved for monotherapy use for partial seizures in the United States. This study provides insight into the feasibility of perampanel monotherapy in real-world settings.. This retrospective, non-interventional, multicentre study (NCT02736162) was conducted between January 2013 and March 2016 in specialist epilepsy centres in Europe and Russia. Eligible individuals had a diagnosis of epilepsy and received perampanel primary or secondary monotherapy as routine clinical care. The primary endpoint was proportion of individuals remaining on perampanel monotherapy, after conversion from perampanel adjunctive treatment, at 3, 6, 12, 18 and 24 months (retention rate).. Sixty individuals were in the safety set (female, 63%; white, 97%; aged 18 to <65 years, 73%). Most (85%) received secondary monotherapy with perampanel. At study cut-off, 68% of individuals were continuing on perampanel monotherapy (secondary monotherapy: 55%). The median duration of retention was not calculable due to the high number of individuals ongoing on monotherapy. Twelve individuals had treatment-emergent adverse events that started during perampanel monotherapy, the most frequent was dizziness (5%). One serious treatment-emergent adverse event was reported (pneumonia during adjunctive perampanel treatment).. In this small retrospective study of individuals who received perampanel monotherapy, the majority maintained monotherapy. Perampanel monotherapy may be an achievable option in some people with epilepsy.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Epilepsy; Female; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

Perampanel (PER) is a third generation antiepileptic drug (AED), recently approved as add-on therapy in both focal and generalized seizures. Levetiracetam (LEV) is a second generation AED, widely used in patients with epilepsy because of its favorable safety and efficacy profiles. Perampanel and LEV treatments have been associated with the occurrence of similar adverse events (AEs) (sleepiness, irritability, depression, anxiety, aggressiveness). The aim of the present retrospective single center study was to verify the efficacy and tolerability of PER and LEV used as first add-on therapy in patients with epilepsy affected by secondarily generalized seizures. We collected data from 15 patients treated with PER and 26 patients treated with LEV and followed at our site with follow-up visits at 3, 6, and 12months. This retrospective study documented the comparable efficacy of PER and LEV as first add-on treatments in patients affected by uncontrolled secondarily generalized seizures. However, more patients withdrawn LEV because of AEs compared with PER at the 3- and 12-month follow-up visits. The better tolerability of PER observed in this study could be related to the low therapeutic dose of PER prescribed when it is used as first adjunctive treatment for better controlling secondarily generalized seizures.

Topics: Adult; Aggression; Anticonvulsants; Anxiety; Depression; Dizziness; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Irritable Mood; Levetiracetam; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome; Wakefulness

This retrospective longitudinal study aims to compare the longer-term cognitive and behavioral side effects of adjunctive antiepileptic treatment with perampanel (PER) and lacosamide (LCM), two third generation antiepileptic drugs with suggested favorable cognitive profiles. The two drugs were monitored according to a previously established routine diagnostic protocol (Helmstaedter et al. E&B 2013;26:182-7) which facilitates the retrospective comparison of antiepileptic drug tolerability in a naturalistic outpatient setting.. Records from 94 patients were evaluated who underwent neuropsychological assessment before and under adjunctive treatment with either PER (n = 57) or LCM (n = 37). Cognition was assessed using the EpiTrack screening for executive functions and a VLMT short form for verbal memory. Subjective assessments included a German QOLIE-10 adaptation (quality of life) and an extended Adverse Events Profile (AEP). The median follow-up interval was 36 weeks.. Multivariate repeated measures statistics revealed a non-significant trend towards an interaction effect "time - treatment arm" on both executive function and memory. When analyzed separately executive functions and memory scores significantly improved under LCM (t = -2.76 p < 0.01 and t = -2.44 p < 0.05 respectively). Subjectively, PER was associated with improvements in 2/18 physiological domains and in the LCM group 1/9 cognitive domains deteriorated. Seizure freedom was achieved for five patients treated with LCM (14%) and 15 treated with PER (26%, χ. In a naturalistic outpatient setting, chronic adjunctive treatment with PER and LCM did not negatively affect cognition and LCM may even improve cognition. Neither drug increased self-reported irritability or aggression. This suggests favorable longer-term tolerability.

Topics: Acetamides; Adult; Anticonvulsants; Cognition; Drug Therapy, Combination; Epilepsy; Executive Function; Female; Follow-Up Studies; Humans; Lacosamide; Longitudinal Studies; Male; Memory; Multivariate Analysis; Neuropsychological Tests; Nitriles; Outpatients; Pyridones; Quality of Life; Retrospective Studies; Treatment Outcome

Topics: Anticonvulsants; Brain Waves; Cognition Disorders; Delirium; Electroencephalography; Epilepsy; Humans; Male; Nitriles; Pyridones

Perampanel is a novel noncompetitive selective antagonist at the postsynaptic ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor, which is approved as an adjunctive agent for the treatment of partial-onset seizure with or without secondary generalization and for primary generalized tonic-clonic seizure in patients with epilepsy who are at least 12 years of age. Limited information is available about the clinical utility of therapeutic drug monitoring of perampanel and therapeutic ranges are so far not established. Therefore, perampanel titration should be performed especially in case of insufficient success of the drug.. The authors developed a selective and sensitive LC-MS/MS (liquid chromatography-mass spectrometry) assay to monitor perampanel concentrations in plasma, which was compared to a commercially available high-performance liquid chromatography kit with fluorescent detection. Perampanel and the internal standard were extracted from plasma samples by a simple protein precipitation. The method allows the simultaneous quantification of perampanel and several other antiepileptic drugs (AEDs).. Data were evaluated according to EMA guidelines for bioanalytical method validation. Extraction recovery of perampanel from human plasma was consistently above 98%. No matrix effect was found. Analytical interferences by other AEDs were not observed. The method was linear in the range from 2.5 to 2800 ng/mL. Intra-assay and interassay reproducibility analyses demonstrated accuracy and precision within acceptance criteria. Data collected from 95 patients, given perampanel as their maintenance antiepileptic therapy, showed a very strong correlation between the 2 methods.. The assay allows for highly sensitive and selective quantification of perampanel and concomitant AEDs in patient plasma samples and can be easily implemented in clinical settings. Our findings are in agreement with previously published data in patients comedicated with enzyme inducer AEDs, but seem to indicate a possible interaction in patients treated with the enzyme inhibitor drug valproic acid.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Chromatography, High Pressure Liquid; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Spectrometry, Fluorescence; Tandem Mass Spectrometry; Young Adult

We report the most notable pharmacokinetic and pharmacodynamic characteristics of the antiepileptic drugs commercialised in the last four years (eslicarbazepine acetate, brivaracetam and perampanel). Their efficacy and safety are analysed in open-label clinical trials, which are the ones that reproduce their use in everyday life, without the rigid protocols used in clinical trials.. Farmacos antiepilepticos.. Se refieren las caracteristicas farmacocineticas y farmacodinamicas mas destacadas de los farmacos antiepilepticos comercializados en los cuatro ultimos años (acetato de eslicarbacepina, brivaracetam y perampanel). Se analiza su eficacia y tolerabilidad en estudios clinicos abiertos, que son los que reproducen su utilizacion en la vida diaria, sin los protocolos rigidos de los ensayos clinicos.

Topics: Anticonvulsants; Dibenzazepines; Epilepsy; Humans; Nitriles; Pyridones; Pyrrolidinones

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Valproic Acid; Young Adult

Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy.. Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed.. Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER.. PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Neoplasms; Disease Progression; Epilepsy; Female; Glioma; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures

To pool observational data on the routine use of perampanel to obtain information on real-world outcomes and data in populations typically underrepresented in clinical trials.. Individual-level data of people with epilepsy treated with perampanel at 45 European centers were merged into a single dataset. Prespecified outcomes were: 1-year retention rate, 1-year seizure freedom rate (duration ≥6 months), and incidence of treatment-emergent adverse events (TEAEs). In addition, relationships were explored with logistic regression analyses.. The full analysis set comprised 2396 people: 95% had focal seizures; median epilepsy duration was 27 years; median number of concomitant antiepileptic drugs (AEDs) was 2; and median prior AEDs was 6. One-year retention rate was 48% (1117/2332; 95% confidence interval [CI] 46-50%), and 1-year seizure-free rate (≥6-month duration) was 9.2% (74/803; 95% CI 7-11%). Median treatment duration was 11.3 months (1832 patient-years); median dose was 8 mg. In 388 individuals with available data at 3, 6, and 12 months, responder rates were 42%, 46%, and 39%, respectively. During the first year, TEAEs were reported in 68% of participants (1317/1497; 95% CI 66-70%). Logistic regression found higher age at perampanel initiation was associated with higher seizure-free rate, and higher number of prior AEDs with lower seizure-free rate and lower rates of somatic TEAEs. In 135 individuals aged ≥65 years, 1-year retention rate was 48% and seizure-free rate was 28%.. Across a large, treatment-resistant population, add-on perampanel was retained for ≥1 year by 48% of individuals, and 9% were seizure-free for ≥6 months. TEAEs were in line with previous reports in routine clinical use, and less frequent than in the clinical trial setting. No new or unexpected TEAEs were seen. Despite the limitations of observational studies, our data indicate that some individuals may derive a marked benefit from the use of perampanel.

Topics: Adult; Age Factors; Anticonvulsants; Datasets as Topic; Epilepsy; Europe; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Middle Aged; Nitriles; Outcome Assessment, Health Care; Pyridones; Regression Analysis; Retrospective Studies; Time Factors

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Fructose; Humans; Lacosamide; Levetiracetam; Male; Medical Audit; Mental Disorders; Middle Aged; Nitriles; Piracetam; Pregabalin; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Sodium Channel Blockers; Topiramate; Young Adult

There is a shortfall of suitably powered studies to provide evidence for safe prescribing of AEDs to people with Intellectual Disability (ID). We report clinically useful information on differences in response to Perampanel (PER) adjunctive treatment for refractory epilepsy between ID sub-groups and general population from the UK Ep-ID Research Register.. Pooled retrospective case notes data of consented people with epilepsy (PWE) prescribed PER from 6 UK centres was classified as per WHO guidance into groups of moderate -profound ID, mild ID and General population. Demographics, concomitant AEDs, starting and maximum dosage, exposure length, adverse effects, dropout rates, seizure type and frequency were collected. Group differences were reported as odds ratios estimated from univariable logistic regression models.. Of the 144 PWE (General population 71, Mild ID 48, Moderate to profound ID 48) examined the association between withdrawal and ID type was marginally statistically significant (p=0.07). Moderate to profound ID PWE were less likely to come off PER compared to mild ID (OR=0.19, CI=0.04-0.92, p=0.04). Differences in mental health side effects by groups was marginally statistically significant (p=0.06). Over 50% seizure improvement was seen in 11% of General population, 24% mild ID and 26% Moderate to profound ID.. PER seems safe in PWE with ID. It is better tolerated by PWE with Moderate to profound ID than PWE with higher functioning. Caution is advised when history of mental health problems is present. The standardised approach of the Ep-ID register UK used confirms that responses to AEDs by different ID groups vary between themselves and General population.

Topics: Adult; Aged; Anticonvulsants; Epilepsy; Female; Humans; Intellectual Disability; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome; Young Adult

Perampanel is a new antiepileptic drug (AED) that acts as a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist and is mainly metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the influence of concomitant AEDs on the serum concentration profile of perampanel.. A total of 215 serum samples obtained from 76 patients aged 12 years or older were analyzed for routine therapeutic drug monitoring, and the concentration-to-dose ratio (CD ratio) of perampanel was compared among patients on various AED regimens.. In patients not taking concomitant enzyme-inducing AEDs, the mean CD ratio was 3963 ng·mL·mg·kg (range: 1793-13,299). By contrast, the mean CD ratio was lower in patients using enzyme-inducing AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range: 473-1853) ng·mL·mg·kg in patients taking phenytoin, phenobarbital, and carbamazepine, respectively], and carbamazepine had a significantly greater reduction in the CD ratio compared with phenytoin or phenobarbital (P < 0.001). Twenty-one patients responded with ≥50% reduction of seizure frequency from baseline, and their mean serum perampanel concentration was 450 ng/mL (range: 85-1500).. There is a large interindividual variation in CD ratio of perampanel because its metabolism is highly susceptible to interactions with enzyme-inducing AEDs. Therapeutic drug monitoring could be clinically useful for determining the influence of AED CYP3A4 inducers on perampanel concentrations.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Humans; Japan; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Young Adult

The purpose of this study was to evaluate changes in health care resource utilization following the initiation of perampanel for the treatment of epilepsy in the United States.. Health care claims from Symphony Health's Integrated Dataverse database between December 2012 and November 2015 were analyzed. Patients newly initiated on perampanel, having ≥1 epilepsy (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 345.xx, ICD-10-CM code G40.xxx) or nonfebrile convulsion (ICD-9-CM code 780.39, ICD-10-CM code R56.9) diagnosis, and having ≥6 months of baseline and observation periods were included. Patients <12 years old at perampanel initiation were excluded.. Of the 2,508 perampanel patients included in the study, the mean [median] (±standard deviation [SD]) age was 35.8 [34] (±16.0) years and 56.2% were female. The mean [median] (±SD) observation duration was 459.8 [462] (±146.3) days in the postperampanel period. The postperampanel period was associated with significantly lower rates of all health care resource utilization outcomes than the pre-period. For the post- versus pre-period, perampanel users had 42.3 versus 53.8 overall hospitalizations per 100 person-years (rate ratio [RR] = 0.80, p < 0.001) and 1,240.2 versus 1,343.8 outpatient visits per 100 person-years (RR = 0.91, p < 0.001). Epilepsy-related hospitalizations and outpatient visits were 25.2 versus 33.6 per 100 person-years (RR = 0.76, p < 0.001) and 327.0 versus 389.0 per 100 person-years (RR = 0.84, p < 0.001), respectively. Additionally, a significantly lower rate of status epilepticus in the post-period (1.8 events per 100 person-years) was observed compared to the pre-period (4.4 events per 100 person-years; RR = 0.43, p < 0.001). The monthly time trend of hospitalizations showed an increasing trend leading up to the initiation of perampanel, after which the hospitalizations decreased steadily.. Use of perampanel for the treatment of epilepsy was associated with significant reduction in all-cause and epilepsy-related health care resource utilization, including hospitalizations, especially for status epilepticus, and outpatient visits.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Anticonvulsants; Child; Epilepsy; Female; Health Services; Hospitalization; Humans; Male; Middle Aged; Nitriles; Pyridones; Status Epilepticus; United States; Young Adult

To analyze the efficacy and safety of perampanel over a 3-month period in a sample of Asian people with epilepsy.. The efficacy and safety of perampanel as an adjunctive therapy for patients with epilepsy were retrospectively reviewed and analyzed. Patients were categorized according to seizure type, concomitant antiepileptic drug usage, and perampanel dosage.. A total of 210 patients were included in the study and 131 patients completed 3 months of perampanel treatment. The average dosage of perampanel was 5.31 mg/day, and the 50% responder rate (≥50% seizure frequency reduction) in all patients was 45.8%, with a 27.5% seizure-free rate. For focal seizures, focal to bilateral tonic-clonic seizures, and primary generalized seizures, the 50% responder rates were respectively 29.4%, 49.5%, and 36.4%. In total, 39.5% of patients experienced adverse events within 3 months of observation period, and the rate of drug withdrawal due to adverse events was 8.6%. Dizziness, ataxia, irritability/aggression were the most common adverse events.. The efficacy and safety of perampanel in a real-world setting with Asian patients is comparable to that in clinical trials that have included fewer Asian patients.

Topics: Adult; Anticonvulsants; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies

To derive clinically useful information about the efficacy and tolerability of adjunctive treatment with perampanel for refractory epilepsy in an outpatient setting.. We pooled retrospective casenotes data of adult patients with refractory epilepsy prescribed perampanel from 18 hospitals throughout UK and Ireland.. Three hundred and ten patients were included (mean age 40.9 [SD=12.0], 50% women, 27.7% with learning disability). The mean duration of epilepsy was 26.7 years (range 2-67 years, SD=13.5) and 91.9% were taking two or more anti-epileptic drugs at the time of perampanel initiation. Mean retention was 6.9 months (range 1 day-22.3 months, SD=4.5). The retention was 86% at 3 months, 71% at 6 months, 47.6% at 12 months and 27% at 18 months. At final follow-up a >50% reduction in seizure frequency was reached in 57.5% of tonic-clonic seizures, 57.4% of complex partial seizures and 43.8% of simple partial seizures. Eleven patients (3.5%) became seizure free. Two hundred and nine patients (67.4%) experienced adverse effects and of these 67% withdrew treatment due to their effects. The most common were sedation, behaviour/mood disturbance, dizziness, and unsteadiness.. Perampanel appears a safe and effective antiepileptic drug when used as adjunctive therapy in patients with uncontrolled partial epilepsy (including those with learning disability), although few patients achieved complete seizure control. Long-term retention was slightly lower than reported rates for other anti-epileptic drugs, potentially due to the highly refractory population. Monitoring for adverse effects on energy levels, mood and behaviour is recommended.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Female; Humans; Ireland; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; United Kingdom; Young Adult

Perampanel (PMP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is a novel anti-epileptic drug (AED) licensed for the adjunctive treatment of focal and generalized epilepsy. There is limited information on PMP's pharmacokinetics and drug interaction characteristics with concomitant AEDs. We have investigated the effects of PMP dose, age, sex, and coprescribed AEDs on serum PMP concentrations.. We used the database of a therapeutic drug monitoring unit at a tertiary epilepsy referral center to identify patients who had PMP as part of their treatment and extracted clinical information from their medical notes. Sera PMP concentrations were determined using liquid chromatography/mass spectroscopy.. In total, 160 sera from 107 patients (66 females) aged 18-70 years and weighing 40-125 kg were identified. They were prescribed a median PMP dose of 6 mg/d (range 2-12 mg/d) and were coprescribed a variety of AEDs, including enzyme-inducing [carbamazepine (CBZ) and oxcarbazepine (OXC)] and enzyme-inhibiting (valproic acid) AEDs. A linear relationship was observed between PMP dose and serum concentrations (r = 0.714, P < 0.0005). Sex and age were found not to influence PMP serum concentration. Enzyme-inducing AEDs dose-dependently decreased PMP concentrations, with CBZ and OXC decreasing mean values by 69% and 37%, respectively. In contrast, although topiramate and phenytoin also decreased mean PMP concentrations by 18% and 13%, respectively, these changes did not achieve statistical significance.. PMP exhibits a linear dose-concentration relationship, with serum PMP concentrations being age and sex independent. CBZ and OXC can significantly decrease PMP concentrations, probably through an induction of CYP3A4-mediated metabolism.

Topics: Adolescent; Adult; Age Factors; Aged; Anticonvulsants; Chromatography, Liquid; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Mass Spectrometry; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Sex Factors; Young Adult

Perampanel, a non-competitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, is the most recent antiepileptic drug available in Spain, marketed in January 2014. It was initially approved by the European Medicines Agency as adjunctive treatment for partial-onset seizures in patients 12 years and older, but recently also for primary generalized tonic-clonic seizures. Although clinical trials provide essential information about the drug, they do not reflect daily clinical practice. This retrospective study shows the initial experience with perampanel in 11 Spanish hospitals during its first year post-commercialisation. All patients who started perampanel treatment were included, but efficacy and tolerability were only assessed in those patients with a minimum follow-up period of six months. In total, 256 patients were treated with perampanel before September 2014, and 253 had an observational period of one year. After six months, 216/256 patients (84%) continued on perampanel and 180/253 (71.1%) completed one year of treatment. The mean number of previous antiepileptic drugs used was 6.83 and the median number of concomitant antiepileptic drugs was 2. The mean perampanel dose was 7.06 mg and 8.26 mg at six and 12 months, respectively. The responder rate was 39.5% and 35.9% at both follow-up points, respectively. Adverse events were experienced by 91/253 (35.5%) and resulted in withdrawal in 37 (14.6%). The most common adverse events were somnolence, dizziness, and irritability. We found no significant differences between concomitant use of enzyme-inducing and non-inducing antiepileptic drugs, regarding efficacy, adverse effects, or withdrawals. Irritability was not influenced by concomitant use of levetiracetam, relative to other drugs, but was more frequently observed in patients with a history of psychiatric problems or learning disabilities.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Dizziness; Epilepsy; Female; Humans; Irritable Mood; Male; Middle Aged; Nitriles; Pyridones; Retreatment; Retrospective Studies; Treatment Outcome; Young Adult

This article describes a monocentric retrospective analysis of clinical experience with the latest antiepileptic drug perampanel with non-competitive modulation of postsynaptic AMPA receptors.. Evaluation of electronic medical charts of patients newly treated with perampanel between 2012 and 2014 at the epilepsy center of the University Hospital Freiburg regarding effectiveness and tolerability.. A total of 85 patients (45 male, mean age 37.4 years, range 14-80 years) with therapy resistance to an average of 6 antiepileptic medications were newly treated with add-on perampanel. Of the patients 35 % experienced a relevant reduction in seizures. The most commonly reported side effects were tiredness (32.5 %), dizziness (24.5 %) and irritability (10.5 %). The dosages resulting in a significant reduction in seizures which varied between patients from 4 to 12 mg/day. Even multidrug-resistant patients who had not benefited from vagus nerve and deep brain stimulation, profited from add-on treatment with perampanel.. In this cohort, even epilepsy patients who did not respond to multiple previous antiepileptic treatment profited from add-on therapy with the new mode of action of perampanel.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome; Young Adult

Perampanel, a new specific non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist, has been recently approved in the United States and the European Union for the adjunctive treatment of focal seizures and primary generalized tonic-clonic seizures associated with idiopathic generalized epilepsy. A positive relationship between plasma perampanel concentration and improvement in seizure control has been identified in regulatory trials, suggesting that therapeutic drug monitoring could be useful in optimizing clinical response in patients with epilepsy treated with perampanel. The development of a simple and broadly applicable method for measuring plasma perampanel concentrations is desirable to permit the use of TDM for this drug in clinical practice.. A high-performance liquid chromatographic method with ultraviolet detection for the quantitative determination of perampanel in small aliquots of human plasma (200 μL) has been developed and validated. Sample preparation involves a simple precipitation step followed by solvent evaporation. High-performance liquid chromatographic separation is achieved on 2 reverse-phase monolithic columns in sequence connected to an ultraviolet detector (320 nm), using as mobile phase water/acetonitrile (60:40 vol/vol) mixed with 1 mL/L phosphoric acid, at a flow rate of 1.5 mL/min. Promethazine hydrochloride is used as internal standard.. Calibration curves were linear over a perampanel concentration range of 25-1000 ng/mL, with correlation coefficients equal or greater than 0.998 ± 0.001 and a limit of quantitation set at 25 ng/mL. Intra- and inter-day coefficients of variation did not exceed 7.4%, and the accuracy ranged from 96.4% to 113.3%. No interference was observed from commonly coprescribed drugs.. The present assay is simple, specific, and cost effective with performance characteristics suitable for TDM use.

Topics: Anticonvulsants; Biological Assay; Calibration; Chromatography, High Pressure Liquid; Drug Monitoring; Epilepsy; Humans; Nitriles; Pyridones; Reproducibility of Results; Seizures; Ultraviolet Rays

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.

Topics: Animals; Anticonvulsants; Benzothiazoles; Calcium Channels; Cerebellum; Convulsants; Disease Models, Animal; Dizziness; Epilepsy; Mice; Nitriles; Pentylenetetrazole; Prosencephalon; Pyrazoles; Pyridones; Rats; Receptors, AMPA; Seizures

Perampanel is a non-competitive antagonist of AMPA glutamate receptors on post synaptic neurons. The aim of this study was to conduct an audit of the experience of perampanel treatment in Ireland based on the interrogation of the national epilepsy electronic patient record (EPR). A retrospective audit was compiled which reviewed the progress of patients who had been treated across two regional epilepsy centres. The EPR was used to identify patients and collect information relevant to their perampanel therapy. Collected data was entered into a statistical package for social sciences for analysis using descriptive statistics. Seventy patients were identified for inclusion in this audit. Partial onset epilepsy was the predominant epilepsy syndrome treated with perampanel. Eight milligrams daily was the maximum dose achieved in 31.45% (n=22). Complex partial seizures demonstrated the best seizure response to perampanel, which was optimal at doses of 4mgs to 8mgs once daily. Treatment was discontinued primarily due to side effect profile (28.5%; n=20). The common side effects reported were behavioural alteration, sedation and dizziness. Abnormal thoughts were identified in 4.2% (n=3). Overall perampanel has been shown to be an effective adjunct. The EPR was demonstrated as an effective tool for audit and research.

Topics: Anticonvulsants; Electronic Health Records; Epilepsy; Humans; Ireland; Medical Audit; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

Clinical data regarding use of antiepileptic drugs in the elderly are generally scarce. Therefore, a subanalysis of subjects aged ≥ 65 years who participated in the 3 phase III perampanel studies was undertaken to determine efficacy and safety in these patients. Efficacy (change in seizure frequency/28 days and 50% responder rate) in the elderly subgroup was found to be consistent with the adult population. Adverse event rates were also largely similar, with some exceptions. Because risks of falls, dizziness, and fatigue were greater in the elderly, careful titration of perampanel in patients aged ≥ 65 years is suggested, especially at higher doses, where balancing tolerability and clinical response is necessary.

Topics: Aged; Anticonvulsants; Clinical Trials, Phase III as Topic; Epilepsy; Female; Humans; Male; Multicenter Studies as Topic; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Anticonvulsants; Epilepsy; Female; Humans; Male; Nitriles; Pyridones; Suicide; Young Adult

With perampanel the first-in-class selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolprepionic acid (AMPA) receptor antagonist has been finally approved for add-on treatment in patients with focal-onset seizures. This suggests additional therapeutic potential in hitherto difficult-to-treat epilepsies.

Topics: Anticonvulsants; Epilepsy; Humans; Nitriles; Pyridones; Receptors, AMPA

The ultimate treatment goal in epilepsy therapy is always freedom from seizures with as few treatment adverse effects as possible. If seizures persist with the first monotherapy, alternative monotherapy with another antiepileptic drug (AED) should be considered. Continuing seizures should lead to a reevaluation of differential diagnosis and adherence. Epilepsy surgery as an alternative therapy may be suitable in selected cases. If the diagnosis of epilepsy is established and epilepsy surgery is not appropriate, AED treatment should be optimized. Evidence for how to proceed is lacking. Concepts such as rational polytherapy have been advocated but remain speculative concerning better efficacy based on the use of AEDs with differing modes of action. A variety of new AEDs including rufinamide, lacosamide, vigabatrin, perampanel, and retigabine have been recently introduced in the United States. They are briefly characterized in this update review.

Topics: Acetamides; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Lacosamide; Nitriles; Pyridones; Receptors, AMPA; Vigabatrin

Perampanel (PER) has been approved for adjunctive treatment of partial-onset seizures in patients age 12 years and older. In Germany, PER was licensed and marketed in September of 2012. At our tertiary referral epilepsy center, a couple of difficult-to-treat patients were awaiting this introduction of PER; therefore, we were able to initiate treatment in many patients within a short period of time. For this report we collected and analyzed the data of the first patients who had been started on add-on PER between September and December of 2012, so that we were able to evaluate at least 6 months of treatment when we made this analysis. At cutoff in June of 2013, 74 patients could be analyzed. Mean age was 38.4 years (range 15-71 years). PER doses ranged from 4 to 14 mg (mean 8.8 mg). All patients took PER once daily at bedtime. Seventy-one patients had focal epileptic seizures; the remaining four patients had Lennox-Gastaut syndrome. Considering the last 3 months of observation compared with baseline, 34 patients (46%) were responders with a reduction of seizure frequency of at least 50%. Ten patients of these (14% of all) were seizure-free. Adverse events were reported in 40 patients (54%). Leading side effects were somnolence (n = 31, 42%) and dizziness (n = 13, 18%), followed by ataxia, irritability, falls, cognitive slowing, and depression in single cases. Six-month retention rate was 70%. Our first clinical experiences with add-on PER in a highly selected group of difficult-to-treat epilepsies are promising.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome

Topics: Administration, Oral; Anticonvulsants; Drug Administration Schedule; Drug Costs; Drug Interactions; Epilepsy; Excitatory Amino Acid Antagonists; Humans; Nitriles; Pyridones; Receptors, AMPA; Treatment Outcome

Perampanel (PER) has been approved by the European Medicines Agency (EMA) for adjunctive treatment of patients with partial-onset seizures from age 12 years on. It has been introduced to the market in Germany and Austria in 2012. This cross-sectional observational study summarizes the clinical experience of nine centers with adjunctive PER. Patients were consecutively followed from the initiation of PER on. Only patients with a minimum observational period of six months (in case of ongoing treatment) were recruited. Efficacy data reflect the preceding three months at last observation, tolerability data were assessed at the last observation carried forward. 281 patients were included. After six months 169 were still on PER so that a retention rate of 60% resulted. 43 patients were seizure-free for the preceding 3 months (15%). Overall incidence of adverse events was 52.0%. The leading adverse events were somnolence (24.6%) and dizziness (19.6%) followed by ataxia (3.9%), aggression (2.8%), nausea (2.5%) and irritability (2.1%). We conclude that adjunctive PER may lead to at least temporary freedom of seizures in some of these highly difficult-to-treat patients. Adverse events are not uncommon.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Austria; Child; Cross-Sectional Studies; Epilepsies, Partial; Epilepsy; Female; Germany; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 μM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 μM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.

Topics: Action Potentials; Adolescent; Animals; Anticonvulsants; Brain; Case-Control Studies; Epilepsy; Humans; Male; Nitriles; Organ Specificity; Pyridones; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Xenopus

Perampanel is one of the latest released antiepileptic drugs (AEDs). Early studies suggest no significant liver enzyme induction from this compound. We report on two patients with medically resistant epilepsy, who had perampanel added to their usual regimen. Both experienced a worsening of their epilepsy and presented in convulsive status epilepticus; concurrent antiepileptic drug levels (phenytoin, phenobarbital, rufinamide) were significantly decreased (<50%) in comparison with levels prior to perampanel introduction. Intravenous load and significant increase of maintenance dosages were needed to restore therapeutic drug levels. In one patient, further increase of perampanel resulted in a new drop of phenytoin level. This suggests that perampanel could, in some subjects, induce liver enzymes and interact with concomitant AEDs; monitoring levels of concomitant compounds could be useful.

Topics: Adult; Anticonvulsants; Epilepsy; Humans; Liver; Male; Nitriles; Pyridones; Young Adult

Topics: Adolescent; Anticonvulsants; Drug Hypersensitivity Syndrome; Epilepsy; Female; Humans; Nitriles; Pyridones; Treatment Outcome

Perampanel (PER) is a novel antiepileptic drug that inhibits the AMPA class of glutamate receptors. It has been available in the UK since September 2012. We undertook a retrospective analysis of efficacy and tolerability of PER in 47 patients with drug-refractory epilepsy attending a regional epilepsy service in the UK.. Demographic and clinical data of patients with refractory epilepsy prescribed PER were collected by review of records. Efficacy, as measured by responder rates (>50% reduction in seizure frequency), retention rates, and adverse effects, was analyzed.. Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. Patients were taking a median of 2 AEDs (range: 1-5) when starting on PER. The median dose of PER was 8 mg (range: 2-12 mg). Thirteen (28%) patients were classed as responders, but no patients experienced sustained seizure freedom. Twenty-one (45%) patients had withdrawn from PER during the study period, with 16 (76%) of them withdrawing due to intolerable adverse effects, 4 due to inadequate seizure control, and 1 due to the combination of both. The most frequent adverse effects requiring withdrawal from PER were behavioral reactions including suicidal ideation (n = 2), aggressive behavior (n = 2), and both (n = 1).. In our experience, PER had a retention rate of 55% and a responder rate of 28%. Psychiatric adverse effects, including suicidal ideation, were the most common reasons for withdrawal.

Topics: Adolescent; Adult; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Male; Medication Adherence; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Suicidal Ideation; Treatment Outcome; Young Adult

The Phase II and Phase III clinical development program of perampanel is providing a wealth of data on the safety and tolerability of this alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an adjuvant treatment for refractory partial-onset seizures. In Phase II dose-finding studies, perampanel was associated with an acceptable tolerability profile up to the maximum evaluated dose of 12 mg/day. Subsequent multinational, multicenter, randomized, double-blind, placebo-controlled Phase III registration studies further supported the tolerability of perampanel across the dose range 2-12 mg/day, with interim data from ongoing extension studies indicating that safety outcomes may be maintained over several years. An analysis of the pooled Phase III data indicated that the frequency of adverse events reported with perampanel generally increased in a dose-dependent manner, and the most common adverse events were dizziness and somnolence. Overall, perampanel has been associated with an acceptable and consistent safety profile that is maintained over long-term settings.

Topics: Anticonvulsants; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Longitudinal Studies; Nitriles; Pyridones; Treatment Outcome

Perampanel (Fycompa - Eisai) is a new antiepileptic drug marketed in the EU. It is licensed for use as adjunctive treatment of partial-onset seizuresi with or without secondarily generalised seizures in patients with epilepsy aged 12 years and older.2 Here we discuss the place of perampanel in the treatment of epilepsy.

Topics: Adolescent; Adult; Anticonvulsants; Child; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Humans; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult

Topics: Anticonvulsants; Clinical Trials, Phase III as Topic; Epilepsy; Humans; Nitriles; Pyridones

Topics: Adult; Anticonvulsants; Drug Approval; Epilepsy; Humans; Nitriles; Pyridones