Associate Director Eisai Ltd., Hatfield, Hertfordshire, UK
Rationale: Perampanel is a once-daily antiseizure medication (ASM) approved in the U.S. for partial-onset seizures (adjunctive and monotherapy) in patients aged ≥ 4 years, and adjunctive treatment of primary generalized tonic-clonic seizures in patients aged ≥ 12 years. Perampanel is currently available in oral formulations (tablet and suspension). A formulation for intravenous (IV) administration is also under development for use in patients when oral intake is temporarily not feasible. The aim of this analysis was to explore whether an IV loading dose of perampanel could achieve rapid steady-state exposures similar to those observed for oral 12-mg/day dosing. Methods: Pharmacokinetic (PK) profiles were simulated for a typical 70-kg patient using two dosing regimens. Day 1: (1) a 36-mg IV loading dose followed by a 12-mg IV dose six hours later (i.e., 48 mg total; four-fold the intended oral maintenance dose) or (2) a 36-mg IV loading dose followed by two 12-mg IV doses at six and 12 hours (i.e., 60 mg total; five-fold the intended oral maintenance dose). Day 2 onward: perampanel 12-mg once daily (QD) orally. Both IV loading/oral maintenance regimens were compared with oral perampanel 12-mg QD dosing (Day 1 onward). Safety was supported from a Phase 1 double-blind, controlled, single-dose study (Study 024) where oral perampanel up to 36 mg was evaluated. Results: Perampanel plasma concentrations rapidly increase following IV dosing to achieve levels similar to those seen at steady state following QD oral dosing (Figure 1). On Day 1, the maximum drug concentration (Cmax) simulated for Regimens 1 and 2 were 93% of the steady-state Cmax 12-mg QD oral dosing (851 ng/mL for both IV regimens vs. 920 ng/mL, respectively), and was higher than Cmax for 12-mg oral dosing on Day 1 (278 ng/mL). The Regimen 2 (five-fold the intended maintenance dose) yielded slightly higher (~1%) concentrations after Day 1 than steady-state Cmax. Area under the plasma concentration–time curve up to 24 hours post dose (AUC0–24h) following IV dosing with Regimen 1 on Day 1 was 82% of AUC0–24h at steady-state with QD oral dosing (14,594 ng h/mL vs. 17,811 ng h/mL, respectively) and higher than AUC0–24h with QD oral dosing on Day 1 (3853 ng h/mL). AUC0–24h following IV dosing with Regimen 2 on Day 1 was 94% of AUC0–24h at steady state with QD oral dosing (16,828 ng h/mL vs 17,811 ng h/mL, respectively). Since perampanel PK are linear, these findings are applicable to other dose levels. Cmax values were also within the ranges observed in Study 024 (452–1196 ng/mL) after a 36-mg single oral dose, which was well tolerated with no deaths or serious adverse events (SAEs) (Table 1). Conclusions: Based on PK simulations, perampanel IV loading doses of four or five times that of the intended oral dose are expected to lead to rapid attainment of therapeutic plasma concentrations, similar to that at steady-state with oral dosing. Although the maximum dose of perampanel is 12 mg/day, safety data indicate that single oral doses of up to perampanel 36 mg are well-tolerated. Funding: Please list any funding that was received in support of this abstract.: