Intravenous Perampanel as an Interchangeable Alternative to Oral Perampanel: A Randomized, Crossover, Phase I Pharmacokinetic and Safety Study

Abstract

Intravenous (IV) drug administration enables treatment of epilepsy when oral administration is temporarily not feasible. Perampanel is a once-daily antiseizure medication currently available as oral formulations. Study 050 (NCT03376997) was an open-label, randomized, single-dose, crossover study to evaluate the interchangeability of oral and IV perampanel in healthy subjects (N = 48). Bioequivalence of single 12-mg doses of IV (30-, 60-, or 90-minute infusion) and oral perampanel, ≥6 weeks apart, was assessed. Analyses indicated bioequivalence of area under the plasma concentration-time curve extrapolated to infinity for 30- and 60-minute IV infusions and oral perampanel doses (geometric mean ratio [90% confidence interval], 0.93 [0.84-1.02] and 1.03 [0.97-1.09], respectively); however, IV maximum observed drug concentration (Cmax ) values were 1.35- to 1.61-fold higher than Cmax . Simulated plasma concentration-time profiles using pooled pharmacokinetic data further supported oral and IV perampanel interchangeability in two scenarios: 12-mg per day IV dosing during a temporary 7-day switch from oral steady-state maintenance therapy, and treatment initiation with 2-mg perampanel. Thirty-four (70.8%) subjects experienced treatment-related adverse events. The IV perampanel safety profile was similar to that of oral perampanel without new safety concerns. Perampanel IV infusions may be a suitable temporary alternative to oral perampanel for treatment maintenance and/or initiation.

Keywords: antiseizure medication; bioavailability/bioequivalence; epilepsy; intravenous; perampanel.

Conflict of interest statement

Z.H., O.M., and P.B. are employees of Eisai Europe Ltd. J.A., L.Y.N., and L.R. are employees of Eisai Inc. Medical writing support, under the direction of the authors, was provided by Laura George, PhD, on behalf of CMC AFFINITY, McCann Health Medical Communications, funded by Eisai Inc., in accordance with Good Publication Practice (GPP3) guidelines.

© 2022 Eisai Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Clinical study design. EOS, end of study; IV, intravenous; R, randomization.

Figure 2

Mean (SD) plasma concentration–time profiles of perampanel following single 12‐mg IV infusions (30, 60, and 90 minutes) and 12‐mg oral tablet administration over (A) 4 hours and (B, C) 72 hours after initiation of dosing. IV, intravenous; SD, standard deviation.

Figure 3

Simulated perampanel plasma concentration–time profiles following switching from oral steady state on day 28 to first perampanel 12‐mg IV infusion on day 29, seventh perampanel 12‐mg IV infusion on day 35, and first day of oral tablet restart on day 36 for (A) 30‐minute IV infusions, (B) 60‐minute IV infusions, and (C) 90‐minute IV infusions, all vs oral tablet at steady state on day 28. IV, intravenous.