Evaluate perampanel PK when administered as an IV infusion relative to oral tablets in an open-label, randomized, crossover study, and assess modeling and simulation results to support use of IV perampanel for treatment maintenance or initiation.

IV formulations of antiepileptic drugs (AEDs) can be used for initiation and maintenance of AED therapy when oral treatment is temporarily not feasible.

Forty-eight subjects were randomized into three cohorts; all received perampanel (12 mg) as single IV infusions (30 [n=20], 60 [n=20], or 90 minutes [n=8]) and single oral tablets. PK parameters, derived using non-compartmental analysis, and safety were assessed. To assess bioequivalence at steady state (interchangeability) and following treatment initiation, a two-compartment model was fitted to the data and used to simulate PK profiles. For interchangeability, simulations included 20 subsets of 50 subjects treated with 12-mg tablets (28 days) before switching to 30-minute infusions (1 week), and then back to oral dosing. For treatment initiation, simulations included 100 subjects: 50 received 2-mg tablets and 50 received IV infusions as first treatment.

Following single-dose administration, bioequivalence between the IV (30- and 60-minute infusions) and tablet formulations was shown for area under the curve (AUC), suggesting both formulations deliver equivalent perampanel doses; maximum concentration (C_max) was higher for IV infusions compared with tablets. Simulations of switch scenarios indicated IV infusions are bioequivalent to tablets with respect to C_max and AUC at steady state. Simulations for treatment initiation showed C_max is higher with 2-mg infusions compared with 2-mg tablets, however, this was not considered clinically relevant. IV infusions were generally well tolerated with a safety profile similar to oral tablets; no infusion-specific site reactions or adverse events were recorded.

Perampanel IV infusions are a suitable alternative to oral tablets for treatment maintenance or initiation when oral dosing is temporarily not feasible. 

Funding: Eisai Inc.