Abstracts

Rationale: Data from four randomized, double-blind Phase III studies were pooled to evaluate the pharmacokinetics of adjunctive once-daily perampanel in patients aged ≥12 years with partial-onset seizures or primary generalized tonic-clonic seizures in idiopathic generalized epilepsy.Methods: Patients with uncontrolled partial-onset seizures received placebo or perampanel 8 or 12 mg/day (studies 304 and 305) or 2, 4, or 8 mg/day (study 306). Patients with idiopathic generalized epilepsy and uncontrolled primary generalized tonic-clonic seizures (study 332) received placebo or perampanel 8 mg/day. Perampanel plasma steady-state concentration data from all studies were pooled for pharmacokinetic analysis. The effect of weight, age, sex, race, liver and renal function markers, dose, seizure type, and presence of concomitant enzyme-inducing antiepileptic drugs (EIAEDs) on the apparent clearance (CL/F) of perampanel were investigated by univariate analysis.Results: 4672 observations from 843 patients treated with perampanel (mean age: 33.9 years; female: 52.2%; Caucasian: 72.8%) were analyzed. Using a one-compartment disposition model, univariate analysis found that perampanel pharmacokinetics were not significantly affected by seizure type, thus validating data pooling. Perampanel pharmacokinetics were linear. Co-administration of cytochrome P450 3A4/5 EIAEDs had a statistically significant effect on increased clearance (carbamazepine: 2.75-fold; oxcarbazepine: 1.92-fold; phenytoin: 1.74-fold; topiramate: 1.23-fold [all effects were significant at P<0.001]), resulting in a similar reduction in perampanel exposure levels. Of the intrinsic factors, female gender was associated with a mean 18% decrease in perampanel clearance (P<0.001); increasing body weight was associated with a small change in clearance (exponent = -0.233; P<0.001). The magnitude of these intrinsic effects, however, was much lower than the inter-individual variability in clearance and, hence, these effects were of no clinical relevance. Perampanel clearance was not significantly affected by the presence of concomitant non-EIAEDs, age, race, or hepatic or renal markers.Conclusions: Perampanel pharmacokinetics were significantly affected by body weight, gender, and the presence of concomitant EIAEDs. However, the effects of gender and body weight were small and the groups overlapped considerably, so the observed effects did not appear to be clinically relevant. Seizure type, age, race, renal function, liver function, or the presence of concomitant non-EIAEDs had no effect. Findings confirmed previous pharmacokinetic analyses of studies 304, 305, and 306. Funding: This study was funded by Eisai Inc.