Abstracts

Rationale: PER, a selective noncompetitive AMPA receptor antagonist, is approved in >35 countries for adjunctive treatment of POS with/without secondarily generalized seizures in patients with epilepsy aged ≥12yr. This analysis reports pharmacokinetics (PK) & pharmacodynamics (PD) of perampanel (PER) as adjunctive therapy in adolescents (12-<18yr) with inadequately controlled partial-onset seizures (POS) (in Study 235). Methods: Study 235 compared the effect of PER vs placebo (PBO) on cognition in adolescents. Adolescent patients who enrolled in Phase II study were receiving 1-3 concomitant antiepileptic drugs (AEDs), with only 1 CYP3A4-inducing AED allowed. Following 1-wk baseline, patients were randomized to once-daily double-blind treatment (6wk titration/13wk maintenance) with PBO or PER 2mg/day uptitrated weekly in 2mg increments to a target dose range of 8-12mg/day, with 4-wk follow-up for patients not entering the open-label extension. Population PK analysis was performed on PER plasma steady-state concentration data in adolescents from Study 235 & 3 Phase III studies. The PK/PD relationship between plasma levels of PER from Study 235, Cognitive Drug Research (CDR) System domains (Power of Attention, Continuity of Attention, Quality of Episodic Memory, Quality of Working Memory, Speed of Memory), Global Cognition Scores, and efficacy were explored. Results: Population PK results were consistent with previous analyses and showed that population estimate of PER apparent clearance following oral administration (CL/F) was 0.729 L/h. Coadministration of CYP3A4-inducing AEDs significantly increased PER CL/F by factors of 2.64 (carbamazepine) and 1.78 (oxcarbazepine or phenytoin), resulting in PER exposure being reduced by similar levels. PK/PD analysis for CDR System cognition score data from 70 PER and 40 PBO patients showed that PER exposure had no effect on CDR Global Score or on domains of Quality of Working Memory or Speed of Memory (Fig.1). Small but significant increases in Power of Attention and Quality of Episodic Secondary Memory, and decreases in Continuity of Attention, were found with an increase in PER exposure. PER administration reduced seizure frequency with an increase in average steady-state concentration (C