Tolerability and safety of perampanel: Two randomized dose-escalation studies

Objectives- To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non-competitive AMPA antagonist, as adjunctive therapy for refractory partial-onset seizures. Materials and methods - Two consecutive, randomized, double-blind, dose-escalation studies recruited adults (18-70 years) with uncontrolled partial-onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8-week dose-titration, 4-week dose-maintenance) with placebo or perampanel (up to 4mg/day, dosed once- or twice-daily). In study 208, patients received placebo or perampanel once-daily (up to 12mg) for 16 weeks (12-week titration, 4-week maintenance). Results - Overall, 153 patients were randomized into study 206 (perampanel twice-daily, n=51; perampanel once-daily, n=51; placebo, n=51). Study 208 included 48 patients (perampanel once-daily, n=38; placebo, n=10). The highest dose in study 206 - 4mg/day - was well tolerated, with similar proportions of patients tolerating once-daily (82.4%) and twice-daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ≥6mg perampanel once-daily in a Kaplan-Meier analysis. In both studies, the most common adverse events were CNS-related; most were of mild/moderate severity. Conclusions - Perampanel was well tolerated across doses of 4-12mg/day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.