Abstracts

Rationale: Perampanel (PER), a selective, noncompetitive AMPA receptor antagonist, has been approved as adjunctive treatment for partial-onset seizures (POS). Safety and tolerability of PER has been well documented in 3 double-blind, randomized, placebo (PBO)-controlled phase III trials. Population pharmacokinetic (PK) analysis has shown that PER exposure is affected by gender. Thus, it is of interest to determine if differences exist in PER efficacy and safety between males and females in a gender subgroup analysis from pooled PER phase III trials.Methods: Patients with refractory POS enrolled in 3 phase III trials were aged 12 yrs and receiving 1-3 concomitant AEDs. Following 6-wk baseline, patients were randomized to once-daily double-blind treatment (6-wk titration, 13-wk maintenance) with PBO or PER 8 or 12mg (studies 304 and 305); or PBO or PER 2, 4, or 8mg (study 306). Study results were pooled, including 719 males (PBO N=220; total PER N=499) and 759 females (PBO N=221; total PER N=538). Population PK and PK/pharmacodynamic (PD) analyses using a model based on plasma concentrations in the phase III trials were reported by actual (last) dose. Efficacy endpoints included percent change from baseline in seizure frequency/28 days and responder rate reported by randomized dose. Treatment-emergent adverse events (TEAEs) were reported by last dose.Results: Demographic and epilepsy-specific medical history characteristics for males and females were similar. Mean age was 34.1 and 35.5yrs, and mean weight was 75.4 and 64.9kg, for males and females, respectively. Patterns of completion and discontinuation in gender subgroups were similar. Population PK showed that PER clearance was slightly, but significantly, affected by gender: apparent clearance was 17% lower in females than in males in a model assuming same fatty body mass. Population PK/PD model showed no difference in PER concentration-response relationship as a function of gender. Efficacy results are shown in Table 1. The magnitude of PER treatment effect relative to PBO for median percent change in seizure frequency/28 days was higher for females than males. Responder rates for females were slightly higher than males. In addition to PK differences, the higher effect in females may have been related to the lower PBO response rate for females compared with males. Very common TEAEs were the same in males and females (Table 2). Dizziness and headache occurred at slightly higher percentages of PER-treated females than males, particularly dizziness at 8 and 12mg.Conclusions: Both male and female subgroups showed improved seizure control with PER 4, 8, and 12mg relative to PBO, with higher efficacy and increased dizziness observed in females compared to males, consistent with greater PER exposure in females. Gender-related differences seen in phase III trials may in part be a result of fixed dose randomization study design. Individualized dosing of PER should be based on clinical response and tolerability.