Abstracts

Rationale: RATIONALE: Perampanel (E2007) is a highly selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist currently in development as adjunctive therapy for patients with refractory partial seizures. This population pharmacokinetic (PK)/pharmacodynamic (PD) analysis describes the PK of perampanel and the relationships between (a) exposure and seizure frequency and (b) exposure and central nervous system (CNS) adverse events (AEs). Methods: In 2 double-blind, placebo-controlled, Phase II studies, adult patients with refractory partial-onset seizures receiving ?3 concomitant antiepileptic drugs (AEDs) were randomized to receive either placebo or adjunctive oral perampanel (Study 1: 1-4 mg/d [QD or divided doses BID], 8-week titration, 4-week maintenance; Study 2: 2-12 mg QD, 12-week titration, 4-week maintenance). Plasma samples taken every 2 weeks during titration and once at the end of maintenance, down-titration, and last visit (Study 1) or at the end of titration and maintenance (Study 2) were analyzed for perampanel using a validated method. Population PK (POPPK) and exposure-response parameters were estimated using non-linear mixed-effect modeling. Patient average perampanel steady-state concentrations were derived from a POPPK model and related to 28-day seizure frequency at scheduled assessment visits (exposure/efficacy analysis) and to the daily occurrence of CNS AEs (exposure/safety analysis). Logistic regression (SAS) was used to analyze the probability of the occurrence of CNS AEs in relation to exposure and other covariates. Results: 176 patients were included in the population PK analysis (median age 42 years, 55% female, 89% Caucasian). Perampanel plasma concentrations were adequately described by a one-compartment disposition model with first-order absorption and elimination. Inter-individual variability was estimated for apparent clearance (CL/F) and apparent volume of distribution (V/F). Overall, perampanel CL/F was 1.33 L/h decreasing slightly from first dose to 1.02 L/h following 20 weeks of treatment and exposure was approximately 2-fold lower in patients co-administered with other AEDs that are strong CYP450 inducers, compared to patients not receiving inducers. PK/PD analyses described a concentration-dependent decrease in 28-day seizure frequency and increased probability of response (50% reduction in seizure frequency from baseline) relative to placebo. Occurrence of CNS AEs increased with perampanel exposure. Conclusions: Perampanel PK can be described by a one-compartment model with first-order disposition. Co-administration of other AEDs that are strong CYP450 inducers decreased exposure to perampanel. Data in this study confirm that perampanel provides concentration-dependent decreases in seizure frequency when co-administered with other AEDs. Based on the results of this study and other studies, 3 Phase III studies and their extension study have commenced and are ongoing. (Support: Eisai Inc)