Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials

Introduction: Perampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled Phase III studies. Methods: The Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6 mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12 mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N = 261). Electrocardiograms were recorded at baseline, Day 7 (post 6 mg dose), and Day 16 (post 12 mg dose). Statistical comparisons were between the highest approved perampanel dose (12 mg) versus placebo, a mid-therapeutic dose (6 mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I 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 perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration-QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses <= 12 mg (N = 1038, total perampanel; and N = 442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas. Results: In the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (Delta Delta) QTcF of 12.15 ms at 4 h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Delta) QTcF versus nominal time curves were comparable between perampanel 12 mg and placebo, with most Delta QTcF values being slightly negative. Healthy subjects receiving perampanel 6 and 12 mg doses for 7 days showed no evidence of effects on cardiac repolarization. Peak Delta Delta QTcF was 2.34 ms at 1.5 h postdose for perampanel 6 mg and 3.92 ms at 0.5 h postdose for perampanel 12 mg. At every time point, the upper 95% confidence limit of Delta Delta QTcF for perampanel 6 and 12 mg was <10 ms. Phase III studies revealed no clinically significant difference between patients with partial seizures treated with perampanel or placebo in QTcF and QTcB values >450 ms, with no dose-dependent increases or large incremental changes from baseline of >60 ms. Regression analysis of individual plasma perampanel concentrations versus corresponding QTc interval values in Phase I thorough QT and Phase III studies demonstrated no relationship between perampanel concentrations and QT interval duration. Conclusion: Treatment with perampanel 6 mg and 12 mg for 7 days did not delay cardiac repolarization in healthy volunteers. In a population analysis of 1480 patients with partial seizures treated with perampanel doses <= 12 mg or placebo, no clinically significant trends in QT interval data were noted. Based on the thorough QT study and evaluations from pooled Phase III studies, there is no evidence of prolonged QT interval duration with perampanel treatment. (C) 2015 The Authors. Published by Elsevier B.V.