Rationale: In the U.S., perampanel is approved 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 being developed for temporary interchangeability with oral dosing in patients initiating or maintaining perampanel treatment. The aim of this pharmacokinetic (PK) modeling and simulation was to explore different loading regimens of IV-administered perampanel to achieve rapid steady-state perampanel exposures followed by daily oral dosing at 4 mg. Methods: Perampanel plasma concentrations in a typical 70-kg patient were simulated for three dosing regimens. Day 1: IV loading dose of 16 mg (i.e. 4-fold the intended maintenance dose) as (1) a single 16-mg infusion, or (2) two 8-mg infusions, 6 hours apart or (3) one 8-mg infusion followed by two 4-mg infusions, all 6 hours apart; all IV infusions were administered as 30-minute constant rate infusions. Day 2 onward: perampanel 4-mg once-daily (QD) orally. All IV loading/oral maintenance dosing regimens were compared with oral perampanel 4-mg QD dosing (Day 1 onward). The safety of oral perampanel at high doses (up to 36 mg) was evaluated in a Phase 1, double-blind, controlled, single-dose study (Study 024) in healthy volunteers. Results: Regimen 1 yields the highest maximum drug concentration (Cmax; 500 ng/mL) of the three regimens, which far exceeds steady-state Cmax (276 ng/mL) predicted following 4-mg QD oral dosing (Figure, Table). Regimen 2 is predicted to result in a lower Cmax (359 ng/mL) compared with Regimen 1. Regimen 3 resulted in a predicted Cmax (301 ng/mL) similar to steady-state Cmax following 4-mg QD oral dosing. Cmax values were also within the ranges observed in Study 024 (mean Cmax: 541.8 and 708.7 ng/mL with 24- and 36-mg single oral doses). AUC0-24 on Day 1 was 87.4, 83.9 and 74.1% of that at steady state for Regimens 1, 2 and 3, respectively. In Study 024, all subjects reported TEAEs following single oral perampanel 24- and 36-mg doses (n=37/37 for both) vs 30.6% (n=11/36) for placebo. However, no deaths or serious adverse events occurred; the most commonly reported TEAEs were somnolence (perampanel 24 mg, 91.9%; perampanel 36 mg, 83.8%; placebo, 5.6%), euphoric mood (perampanel 24 mg and 36 mg, both 45.9%; placebo: 8.3%) and dizziness (perampanel 24 mg, 48.6%; perampanel 36 mg, 59.5%; placebo, 5.6%). Conclusions: Based on PK simulations, administering 16 mg of perampanel on Day 1 of treatment as a single or as two 8-mg IV infusions 6 hours apart is predicted to result in greater Cmax values compared with 4-mg oral dosing at steady state. Dividing the loading dose into three IV infusions of 8, 4 and 4 mg, each 6 hours apart is predicted to result in a similar Cmax to that achieved after 4-mg QD oral dosing. Although the maximum intended dose of perampanel is 12 mg/day, single-dose administration of up to 36 mg has been shown to be safe in a previous study. Funding: Please list any funding that was received in support of this abstract.:
