Abstracts

Rationale: Perampanel (PER) is a selective, noncompetitive AMPA-antagonist approved as adjunctive treatment for partial-onset seizures (POS). To assess potential for prolonged cardiac repolarization, a thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled phase III studies.Methods: Thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of PER (6mg once daily for 7 days, followed by dose escalation of single 8mg dose, single 10mg dose, then 12mg once daily for 7 days), moxifloxacin positive control (single 400mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N=261). Electrocardiograms (ECGs) were recorded at baseline, Day 7 (post 6mg dose), and Day 16 (post 12mg dose). Statistical comparisons were between the highest approved PER dose (12mg) vs placebo, a mid-therapeutic dose (PER 6mg) vs placebo, and moxifloxacin vs placebo. Acknowledging that the thorough QT study could not incorporate a true supratherapeutic dose due to length of titration and tolerability concerns in healthy subjects, phase III studies of PER included expanded ECG safety evaluations for concentration-QT response modeling. PER effect on QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, phase III studies with PER doses 12mg (N=1480) in patients with POS. QT measures were corrected for heart rate (QTc) using Fridericia s (QTcF) and Bazett s (QTcB) formulas.Results: In the thorough QT study, moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected ( ) QTcF effect of 12.15msec at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. PER 6 and 12mg doses for 7 days did not show effects on cardiac repolarization in healthy subjects. Peak QTcF effect was 2.34msec at 1.5h postdose for PER 6mg and 3.92msec at 0.5h postdose for PER 12mg. At all time points, upper 95% CL of QTcF for PER 6 and 12mg was <10msec. Mean baseline-adjusted ( ) QTcF vs nominal time curves were comparable between PER 12mg and placebo, with most QTcF values negative (Fig 1). Phase III studies revealed no clinically significant difference between placebo and PER groups in QTcB and QTcF values >450msec, with no dose-dependent increases or large incremental changes from baseline of >60msec. Regression analysis of individual PER plasma concentrations vs corresponding QTc interval values in thorough QT and phase III studies demonstrated no relationship between PER concentrations and QT interval duration.Conclusions: High-therapeutic (12mg) and mid-therapeutic (6mg) doses of PER for 7 days did not prolong cardiac repolarization in healthy volunteers. In a population analysis of 1480 patients with POS treated with placebo or PER doses 12mg, no trends in QT interval data or other ECG parameters were noted. Based on the thorough QT study and evaluations from pooled phase III studies, there is no evidence of increased QT interval duration with PER.