levetiracetam and Kidney-Diseases

Augmented renal clearance (ARC) has been reported in approximately 30-65% of patients in the intensive care unit (ICU) despite the presence of a normal serum creatinine concentration. In certain ICU patient populations (e.g., patients with sepsis or trauma), the incidence increases to roughly 50-85%. Risk factors for ARC include the following: age younger than 50-55 years, male sex, higher diastolic blood pressure, fewer comorbidities, and a lower Acute Physiology and Chronic Health Evaluation II (APACHE II) or modified Sequential Organ Failure Assessment (SOFA) score at ICU admission. In addition, patient populations with the highest reported incidence of ARC include those with major trauma, sepsis, traumatic brain injury, subarachnoid hemorrhage, and central nervous system infection. Due to the high incidence of ARC in patients with a normal serum creatinine concentration, clinicians should consider screening ICU patients deemed high risk by using the ARC scoring system or the identification and assessment algorithm provided in this review. In addition, an 8-hour continuous urine collection should be considered to assess a measured creatinine clearance for evaluating the necessity of medication dosage adjustments. There is a clear association between ARC and subtherapeutic antibiotic concentrations as well as literature suggesting worse clinical outcomes; thus, the risk of underdosing antibiotics in a patient with ARC could increase the risk of treatment failure. This review examines strategies to overcome ARC and summarizes current pharmacokinetic and pharmacodynamic literature in patients with ARC in an effort to provide dosing guidance for this patient population.

Topics: Anti-Bacterial Agents; Creatinine; Critical Illness; Drug Administration Schedule; Humans; Kidney Diseases; Levetiracetam; Piracetam; Pyridines; Renal Elimination; Risk Factors; Thiazoles

Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward.

Topics: Adult; Aged; Anticonvulsants; Chemical Phenomena; Chemistry, Physical; Child; Drug Interactions; Drug Monitoring; Humans; Kidney Diseases; Levetiracetam; Liver Diseases; Piracetam

This review discusses the safety and tolerability of levetiracetam, as presented by the available literature, with attention paid to special populations. In Phase II/III trials, the adverse effects occurring more commonly in the treatment groups versus the placebo group were; somnolence (14.8 versus 8.4%), asthenia (14.7 versus 9.1%), infection (primarily common cold) (13.4 versus 7.5%), and dizziness (8.8 versus 4.1%). Adverse events usually appear within the first month after treatment initiation, are not dose-dependent, are mostly mild-to-moderate, generally resolve without medication withdrawal, and are transient when the medication is stopped. No significant changes in haematology and chemistry profiles or weight occurred. Hypersensitivity reactions were rare and no idiosyncratic event has been reported. Open-label studies have added patient data with other epileptic syndromes and from a wider patient pool, such as children and patients with prior psychiatric history. These studies have supported initial safety findings, but have reported increased behavioural adverse events in children and patients with a history of prior behavioural problems. Levetiracetam is proving to be safe and well-tolerated. So far, it appears to have a favourable safety profile in special populations, such as children, the elderly, and patients with hepatic dysfunction. Preliminary data in pregnancy are promising, but more data are needed on the impact of levetiracetam on the developing fetus and pharmacokinetic alterations caused in pregnancy. Adjustments in dosing are required for decreases in renal clearance.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Age Factors; Aged; Animals; Anticonvulsants; Asthenia; Bone Density; Child; Child Behavior Disorders; Clinical Trials as Topic; Disorders of Excessive Somnolence; Dizziness; Drug Evaluation, Preclinical; Epilepsy; Female; Headache; Humans; Infections; Kidney Diseases; Levetiracetam; Liver Diseases; Male; Mental Disorders; Mice; Middle Aged; Patient Acceptance of Health Care; Piracetam; Pregnancy; Pregnancy Complications

Levetiracetam is a novel orally active antiepileptic drug with a unique preclinical profile. It has a high therapeutic index and potential antiepileptogenic effects. Results of clinical trials indicate activity in partial-onset and generalized seizures. The pharmacokinetic profile of levetiracetam closely approximates the ideal characteristics expected of an antiepileptic drug, with good bioavailability, rapid achievement of steady-state concentrations, linear and time-invariant kinetics, minimal protein binding, and minimal metabolism. The major metabolic pathway of levetiracetam is not dependent on the hepatic cytochrome P450 system, and levetiracetam does not inhibit or induce hepatic enzymes to produce clinically relevant interactions. Sixty-six percent of an administered levetiracetam dose is eliminated unchanged in urine; 24% is metabolized to an inactive metabolite that is detectable in blood and is also excreted in urine. Total body clearance of levetiracetam is decreased in patients with renal impairment, and doses should be modified according to creatinine clearance values. Levetiracetam is not appreciably protein-bound, nor does it affect the protein binding of other drugs. Thus, because of its minimal protein binding and lack of hepatic metabolism, the risk of drug interactions is very low. Levetiracetam has a wide margin of safety and patient-friendly pharmacokinetics that distinguish it from other currently available antiepileptic drugs. This profile may facilitate the clinical management of patients with epilepsy by providing a safer and less-complicated therapeutic strategy.

Topics: Absorption; Adolescent; Adult; Aged; Anticonvulsants; Child; Cytochrome P-450 Enzyme System; Drug Interactions; Epilepsy; Humans; Kidney Diseases; Levetiracetam; Liver Diseases; Middle Aged; Piracetam; Therapeutic Equivalency

Compared with traditional antiepileptic drugs, levetiracetam has a unique mechanism of action and unique properties, including predominant renal excretion and lack of drug-drug interactions. In the elderly, depression associated with levetiracetam has not been reported.. A 73-year-old black man (height, 172.7 cm; weight, 92.7 kg; body mass index [BMI], 31 kg/m(2)) with stage 4 kidney disease was taking levetiracetam 500 mg BID for partial complex seizures. After 5 months of taking medication, new-onset depression, evidenced by depressed mood, weight loss, fatigue, and appearing withdrawn, was noted in this patient. Levetiracetam was discontinued by order of the patient's primary care physician. At a follow-up appointment 4 weeks later, the depressive symptoms had nearly resolved. The patient's Naranjo Adverse Drug Reaction Probability Scale score was 6, indicating levetiracetam to be a probable cause of depression in this patient. In a second case, a 92-year-old white woman (height, 154.9 cm; weight, 54.5 kg; BMI, 22.7 kg/m(2)) with existing chronic kidney disease and new-onset partial seizure, likely due to a meningioma, was initiated on levetiracetam 500 mg once daily. Depressive symptoms (eg, anhedonia, hypersomnolence, decreased appetite) were noted within 5 weeks. Cessation led to improvement in mood and cognition within 8 days. Based on this patient's Naranjo Adverse Drug Reaction Probability Scale score of 6, levetiracetam was a probable cause of depression in this patient.. Levetiracetam was a probable cause of depression in these 2 elderly patients. Cautious use and additional monitoring may be necessary when prescribing levetiracetam to elderly patients, especially when prescribing to those with a history of renal impairment.

Topics: Aged; Aged, 80 and over; Anticonvulsants; Chronic Disease; Depression; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Kidney Diseases; Levetiracetam; Male; Piracetam