Abstracts

Rationale: The potential for liver toxicity is a concern in the antiepileptic drug (AED) class. Perampanel (PER), a selective, noncompetitive AMPA receptor antagonist, has been approved as adjunctive treatment for partial-onset seizures (POS). The safety and tolerability of PER has been well documented in 3 double-blind, randomized, placebo-controlled phase III trials. Here we report the effects of PER on liver function to assess the potential for liver toxicity.Methods: Patients with refractory POS enrolled in the 3 phase III trials were aged 12 years and receiving 1-3 concomitant AEDs. Following 6-week baseline, patients were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with placebo or PER 8 or 12mg (studies 304 & 305); or with placebo or PER 2, 4, or 8mg (study 306). These study results were pooled, including 1038 subjects who received PER and 442 who received placebo. Clinical laboratory tests were performed at baseline and at end of treatment. Hepatobiliary laboratory parameters included alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), and total bilirubin. Hepatobiliary laboratory data were summarized through descriptive statistics, shift tables relative to laboratory normal range, and treatment-emergent markedly abnormal values (increase from baseline to NCI grade 2). Treatment-emergent adverse events (TEAEs) related to hepatobiliary parameters were also recorded.Results: Mean hepatobiliary values (ALT, alkaline phosphatase, AST, GGT, and total bilirubin) were within normal ranges at baseline and end of treatment for placebo and all PER groups. Mean changes from baseline to end of treatment were small. Shifts in values from baseline to end of treatment for the hepatobiliary parameters, relative to normal ranges, revealed no shifts of clinical concern. Markedly abnormal results were very low for placebo and PER, with no dose-related trends and slightly higher rates observed for PER (Table 1). TEAEs related to hepatobiliary parameters occurred in 0% of placebo subjects and 1.2% of subjects who received PER. Hepatobiliary disorders included cholelithiasis (PER 4mg=1 subject; 8mg=1; 12mg=1) and abnormal hepatic function (PER 4mg=1 subject). None of the events were serious, and no PER-treated subjects discontinued due to TEAEs related to hepatobiliary parameters. Subgroup analysis of hepatobiliary data by concomitant AED showed no meaningful differences with any specific AED. No subject had values that met the criteria for Hy s Law (i.e., ALT or AST > 3x upper limit of normal (ULN), alkaline phosphatase < 2x ULN, and total bilirubin > 2x ULN at the same visit).Conclusions: PER doses of 2, 4, 8, and 12mg demonstrated no clinically important effects on liver function tests, indicating low potential for liver toxicity. Hepatobiliary laboratory data and related TEAEs showed no notable differences between placebo and PER treatment groups and no dose-related trends.