Abstracts

Rationale: Perampanel is an orally active, non-competitive AMPA receptor antagonist, which is being evaluated as add-on therapy in patients with refractory partial seizures. We report results from a population pharmacokinetic (pop PK) and pharmacokinetic/pharmacodynamic (PK/PD) analysis from three randomized, double-blind, placebo-controlled phase III trials (studies 304, 305 and 306 [ClinicalTrials.gov identifiers: NCT06699972, NCT06699582, and NCT00699582]).Methods: Studies were conducted in patients (?12 years) with refractory partial seizures, taking 1-3 concomitant antiepileptic drugs (AEDs). Following a 6-week Baseline Phase, patients were randomized to once-daily double-blind treatment (6-week Titration, 13-week Maintenance) with: placebo, perampanel 8 mg, or perampanel 12 mg (1:1:1) in studies 304 and 305; and placebo, perampanel 2 mg, perampanel 4 mg or perampanel 8 mg (1:1:1:1) in study 306. Pop PK and PK/PD relationships were estimated using non-linear mixed-effect modeling. Models were validated using goodness-of-fit plots and visual predictive check (VPC). Modeling of pop PK and PK/PD relationships were performed using NONMEM v5.1 with FOCE estimation. Logistic regression (SAS 8.2) was used to analyze the probability of response and the occurrence of AEs in relation to exposure.Results: Of 1491 randomized patients, 770 were included in the pop PK analysis. Perampanel PK was adequately described by a one-compartment disposition model. Perampanel apparent clearance (CL/F) was lower in females compared with males (0.605 L/h vs 0.730 L/h); this difference is unlikely to be clinically relevant. The PK of perampanel was similar between adolescents and adults, and no significant inter-racial differences were observed. Perampanel CL/F increased approximately 2-fold when co-administered with oxcarbazepine or phenytoin, and 3-fold with carbamazepine. Co-administration of other AEDs did not affect perampanel clearance and perampanel had no clinically relevant effects on the PK of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid, and zonisamide. The PK/PD population included 1109/1491 patients. Seizure frequency decreased with an increase in average exposure to perampanel at steady state, and the probability of an individual to be a responder increased significantly with an increase in exposure to perampanel. Concomitant AEDs had no effect on the exposure/efficacy relationship for seizure frequency or the probability of response. The decrease in seizure frequency was not affected by gender, body mass, age, race, or region. The probability of occurrence of fatigue, somnolence, gait disturbances, dizziness, weight increase, irritability, dysarthria, and euphoric mood increased with increased perampanel exposure.Conclusions: Perampanel PK was described by a one-compartment model with first-order elimination. An exposure/efficacy relationship and increased probability of a response with increasing exposure to perampanel were confirmed. Support: Eisai Inc.