The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist

Abstract

SUMMARYThe clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5 h later; its bioavailability is~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2-12 mg); perampanel is 95% protein-bound to albumin and a1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, halflife decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.

Comparative Bioavailability of Two Oral Perampanel Formulations in Healthy Subjects: A Randomized, Open Label, Single-Dose, 2-Way Crossover Study

“…Parameters of bioavailability observed in this study are consistent with a previous perampanel population (pop) PK analysis based on phase I studies carried out in healthy subjects using a two-compartment model with first-order absorption [6]. When perampanel is administered as a single oral dose in a 12-mg film- coated tablet formulation to healthy subjects (n=45) under fasting condition, mean ± SD (range) pop PK parameters corresponding to C max and AUC inf are estimated in 335.7 ± 119.8 ng/ml (5331-61986) and 21033 ± 10034 ng/ml (5331-61986) ng * h/ml, respectively [6,11].…”

“…Perampanel oral film-coated tablet formulations were developed to enhance patient adherence to treatment. A hallmark of perampanel is its long half-life allowing just a one daily dose which contribute to the patient drug compliance [6]. The maximum recommended daily dose of perampanel is 12 mg being initiated with a daily dose of 2 mg.…”

“…Several single and multi-dose Pharmacokinetics (PKs) studies have been conducted both in healthy subjects and in epilepsy patients [6,8]. Perampanel has a mean oral absolute bioavailability of 100%…”

Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures

“…Based on population PK modeling, perampanel apparent clearance was 17% lower in female than in male participants not receiving concomitant EIAEDs, and it remained somewhat lower with concomitant EIAEDs, implying greater perampanel systemic exposure in females. The PK of perampanel includes a half‐life of ~105 h as well as rapid and almost complete absorption following oral administration 7, 16. Physiologic gender differences may contribute to the lower perampanel CL/F in female patients and may be associated with greater perampanel systemic exposure.…”

Analysis of the clinical experience with perampanel in the Moscow Region: Efficacy, tolerability, individual choice priorities

“…Уникальность ПЕР заключа-ется в его механизме действия, не повторяющемся в других современных ПЭП. Препарат является единственным селе-ктивным неконкурентным (не может быть конкурентно вы-теснен глутаматом) антагонистом ионотропных АМПА-глутаматных рецепторов постсинаптической мембраны нейрона, которым отводится главная роль в процессах гене-рации и распространения возбуждения в ЦНС [4,5]. Связы-ваясь с АМПА-рецептором, ПЕР надежно блокирует его до-ступность для возбуждающих влияний глутамата, тем са-мым препятствуя возникновению и распространению эпи-лептического возбуждения [4,6].…”