Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy

Abstract

Objective: Evaluate the impact of concomitant enzyme (CYP3A4)-inducer antiepileptic drugs (EIAEDs) on the efficacy and safety of perampanel in patients from the 3 phase-III clinical trials.

Methods: Patients with pharmacoresistant partial-onset seizures in the 3 phase-III clinical studies were aged 12 years and older and receiving 1 to 3 concomitant antiepileptic drugs. Following 6-week baseline, patients were randomized to once-daily, double-blind treatment with placebo or perampanel 8 or 12 mg (studies 304 and 305) or placebo or perampanel 2, 4, or 8 mg (study 306).

Results: Treatment response assessed by median percent reduction in seizure frequency and responder rates improved with perampanel compared with placebo. However, at 8 and 12 mg, the treatment response was significantly greater in patients receiving non-EIAEDs. The treatment effect (perampanel-placebo) also demonstrated a dose-dependent increase in all patients. The overall incidence of treatment-emergent adverse events was similar regardless of the presence of EIAEDs. Occurrence of some adverse events, such as fatigue, somnolence, dizziness, irritability, was greater in patients receiving non-EIAEDs, as was discontinuation because of adverse events.

Conclusions: Perampanel shows efficacy and safety in the presence and absence of EIAEDs. As systemic exposure to perampanel increases, so does efficacy. Given the extensive metabolism of perampanel, systemic exposure is clearly reduced with concomitant administration of CYP3A4 inducers. This supports the strategy of dosing perampanel to clinical effect. Recognition of these pharmacokinetic interactions will be important in the optimization of this novel medication.

Classification of evidence: This study provides Class II evidence that 2 to 12 mg/d doses of perampanel reduced seizure frequency and improved responder rate in the presence and absence of EIAEDs.

Figure 1. Treatment response in completers by actual (last) perampanel dose (studies 304, 305, and 306)

(A) Median percent reduction in seizure frequency per 28 days from baseline over double-blind period. (B) Responder rate during maintenance period. Excludes patients from Central and South America and perampanel 6 and 10 mg. EIAEDs include carbamazepine, oxcarbazepine, or phenytoin. ^aOverall placebo is shown in graph; actual placebo median percent reduction in seizure frequency for each dose group was used for statistical analysis (EIAED placebo: 2 mg = 10.1, 4 mg = 10.1, 8 mg = 8.7, 12 mg = 5.8; non-EIAED placebo: 2 mg = 12.7, 4 mg = 12.7, 8 mg = 15.3, 12 mg = 15.9). ^bOverall placebo is shown in graph; actual placebo responder rate for each dose group was used for statistical analysis (EIAED placebo: 2 mg = 18.1, 4 mg = 18.1, 8 mg = 19.4, 12 mg = 20.6; non-EIAED placebo: 2 mg = 19.4, 4 mg = 19.4, 8 mg = 17.1, 12 mg = 15.0). *p < 0.05; **p < 0.01 vs placebo for each dose; †p < 0.05; ‡p < 0.005 EIAEDs vs non-EIAEDs for each dose based on rank analysis of covariance (for median percent reduction) and χ² test (responder rate). EIAED = enzyme (CYP3A4)-inducing antiepileptic drug; N = number of patients in each group.