ritonavir and Seizures

Lopinavir/ritonavir (LPV/RTV) is a CYP3A4 inhibitor and substrate; it also may induce cytochrome P-450 (CYP) isozymes. Phenytoin (PHT) is a CYP3A4 inducer and CYP2C9/CYP2C19 substrate. This study quantified the pharmacokinetic (PK) drug interaction between LPV/RTV and PHT. Open-label, randomized, multiple-dose, PK study in healthy volunteers. Subjects in arm A (n = 12) received LPV/RTV 400/100 mg twice daily (BID) (days 1-10), followed by LPV/RTV 400/100 mg BID + PHT 300 mg once daily (QD) (days 11-22). Arm B (n = 12) received PHT 300 mg QD (days 1-11), followed by PHT 300 mg QD + LPV/RTV 400/100 mg BID (days 12-23). Plasma samples were collected on day 11 and day 22; PK parameters were compared by geometric mean ratio (GMR, day 22:day 11). P values <0.05 were considered significant. Following PHT addition, LPV area under the concentration-time curve (AUC0-12h) decreased from 70.9 +/-37.0 to 49.6 +/- 25.1 microg.h/mL (GMR 0.67, P = 0.011) and C0h decreased from 6.0 +/- 3.2 to 3.6 +/- 2.3 microg/mL (GMR 0.54, P = 0.001). Following LPV/RTV addition, PHT AUC0-24h decreased from 191.0+/-89.2 to 147.8+/-104.5 microg.h/mL (GMR 0.69, P = 0.009) and C0h decreased from 7.0+/-4.0 to 5.3+/-4.1 microg/mL (GMR 0.66, P = 0.033). Concomitant LPV/RTV and PHT use results in a 2-way drug interaction. Phenytoin appears to increase LPV clearance via CYP3A4 induction, which is not offset by the presence of low-dose RTV. LPV/RTV may increase PHT clearance via CYP2C9 induction. Management should be individualized to each patient; dosage or medication adjustments may be necessary.

Topics: Adult; Anticonvulsants; Cytochrome P-450 Enzyme System; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pharmacogenetics; Phenytoin; Pyrimidinones; Ritonavir; Seizures

Topics: Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Epilepsy; Humans; Retrospective Studies; Ritonavir; Seizures

Topics: Betacoronavirus; Brain; Coronavirus Infections; COVID-19; Drug Combinations; Humans; Lopinavir; Male; Middle Aged; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2; Seizures; Treatment Outcome

Topics: Anticonvulsants; Antiviral Agents; Atazanavir Sulfate; Betacoronavirus; Carbamazepine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Humans; Lopinavir; Pandemics; Phenytoin; Pneumonia, Viral; Ritonavir; SARS-CoV-2; Seizures

Topics: Blood Component Transfusion; Contraindications; Drug Interactions; Fever; Fluid Therapy; Hallucinogens; HIV Protease Inhibitors; HIV Seropositivity; Humans; Intensive Care Units; Male; N-Methyl-3,4-methylenedioxyamphetamine; Renal Dialysis; Respiration, Artificial; Ritonavir; Seizures; Survival; Unconsciousness; Young Adult

The authors describe a patient with known human immunodeficiency virus (HIV)-1 infection who presented with two generalized seizures and was found to have extensive white matter disease and a left/bilateral temporo-occipital focal slowing on electroencephalography (EEG). There were no magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) indications for opportunistic infection. Plasma viremia was controlled, whereas viral replication was uncontrolled in CSF. CSF-specific genotype-guided adaptation of the antiretroviral therapy in order to optimize central nervous system (CNS) penetration resulted in clinical improvement and normalization of MRI and EEG. Our case report illustrates the importance of individualized antiretroviral therapy in HIV infected patients with neurological complications.

Topics: Adenine; Adult; AIDS Dementia Complex; Alkynes; Anti-HIV Agents; Anticonvulsants; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cerebrospinal Fluid; Cyclopropanes; Didanosine; HIV-1; Humans; Indinavir; Lamivudine; Male; Nelfinavir; Nevirapine; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Seizures; Stavudine; Tenofovir; Viral Load; Virus Replication; Zidovudine

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antidepressive Agents, Second-Generation; Benzoxazines; Bupropion; Cyclopropanes; Drug Therapy, Combination; HIV Infections; Humans; Male; Middle Aged; Nelfinavir; Oxazines; Retrospective Studies; Ritonavir; Seizures

Topics: Adult; Anticonvulsants; Ataxia; Carbamazepine; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Male; Ritonavir; Seizures; Sleep Stages; Vertigo

Topics: Alkynes; Anti-HIV Agents; Anticonvulsants; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamazepine; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Middle Aged; Mixed Function Oxygenases; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Seizures