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.

Intravenous perampanel as an alternative to the oral formulations in Japanese patients with epilepsy

“…The demographics of healthy subjects were generally similar across IV infusion arms. Overall, 52.1% of the healthy subjects were male, with a mean (standard deviation [SD]) age of 39.0 (9.4) years 17 . Demographics and baseline clinical characteristics of healthy subjects stratified by race, are shown in Table S1.…”

“…Healthy adult subjects aged 20‐55 years with a body mass index of 18‐32 kg/m 2 were eligible to participate in this study. Briefly, key exclusion criteria included pregnancy, clinically significant illness requiring medical treatment within 8 weeks of dosing, clinically significant infection or disease that may influence the outcome of the study within 4 weeks of dosing, a history of gastrointestinal surgery that may affect PK profiles of perampanel, and any clinically abnormal symptom found at screening via medical history and physical examination 17 …”

“…The design of Study 050 has been previously described 17 . Briefly, Study 050 comprised a Prerandomization/Pretreatment Phase (including a Screening and a Baseline Period) and a Randomization/Treatment Phase (including Treatment Periods 1 and 2).…”

“…A Washout Period of 6 weeks or more was introduced between the two treatment periods (Figure 1A). 17 …”

“…Study 240 evaluated the safety, pharmacokinetics (PK), and maintenance of efficacy of 30‐minute IV perampanel (8, 10, or 12 mg/day) as an alternative to oral perampanel in 21 Japanese patients with epilepsy who were receiving marketed perampanel oral tablets. Study 050 assessed the bioavailability of a single 12‐mg dose of IV perampanel of different durations (30‐, 60‐, and 90‐minute) relative to a single 12‐mg dose of perampanel tablets in healthy subjects of mixed ethnicity, 17 where we conducted a subgroup analysis in Japanese subjects. This analysis aimed to evaluate IV perampanel as an alternative to oral perampanel for treatment initiation and/or maintenance, based on data from Studies 240 and 050.…”