Abstracts

Rationale: Perampanel (E2007) is an oral, noncompetitive, highly selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist. Perampanel is currently being investigated in phase III clinical trials in patients with refractory partial-onset seizures. The objectives of the 2 phase I trials presented here were to determine the pharmacokinetics and safety of once- and multiple-daily dosing of perampanel in healthy male subjects. Methods: The first trial assessed the single-dose profile of perampanel and used a randomized, double-blind, placebo-controlled, sequential, ascending single-dose design with 8 subjects per dose-group and doses of 0.2, 0.5, 1, 2, 4, 6, and 8 mg. The second trial evaluated the steady-state profile of perampanel and had a randomized, double-blind, placebo-controlled, multiple-dose, parallel-group design with 4 cohorts of 8 subjects, 6 per cohort receiving perampanel (1, 2, 4, or 6 mg according to cohort) and 2 receiving placebo once daily for 14 days. Both trials enrolled healthy male subjects aged 18-45 years. Sedative effects were assessed using the Bond & Lader visual analog mood scales, saccadic eye movements, and neuropsychological tests. Safety assessments included adverse events (AEs), physical examinations, laboratory tests, and 12-lead electrocardiograms (ECGs). Results: Perampanel reached maximal plasma concentration by about 1 hour and was associated with a mean t_½ ranging from 52-129 hours in the single-dose study and from 66-90 hours in the multiple-dose study. Steady-state plasma concentrations were reached by Day 14 in the multiple-dose study. Sedative effects were observed at doses ≥2 mg; these were dose-dependent and corresponded to peak plasma concentrations of perampanel. In the multiple-dosing study, these effects remained similar on Day 14 despite increased perampanel exposure vs. Day 1. The most common AEs in both studies were dizziness, fatigue, and somnolence. No subjects were withdrawn from the single-dose study. Two subjects receiving perampanel 4 mg in the multiple-dose study were withdrawn because of severe somnolence and vertigo in one case and severe vertigo in the second case; these events resolved with no further sequelae. No serious AEs were reported in either study. In the multiple-dosing study, elevated liver enzymes (≤3X ULN with no apparent relationship to dose) were observed in 12 subjects administered perampanel and in 4 who received placebo. No other changes in physical examinations, vital signs, ECGs, or laboratory tests were observed in either study. Conclusions: Perampanel was rapidly absorbed and slowly eliminated with steady-state being reached by Day 14. Perampanel was well tolerated, with most AEs being mild to moderate in severity. (Support: Eisai Inc.)