Perampanel 6 mg · Tablets

Perampanel is a non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal over excitation.

The precise mechanism by which perampanel exerts its antiepileptic effects in humans is unknown.

Pharmacokinetics of perampanel are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures. The half-life of perampanel is about 105 hours, so that steady state is reached in about 2 to 3 weeks. AUC of perampanel increased in a dose-proportional manner after single-dose administration of 0.2 mg to 12 mg tablets and after multiple-dose administration of 1 mg to 12 mg tablets once daily.

Perampanel oral suspension has comparable bioavailability to perampanel tablets under steady state. Both formulations may be used interchangeably.

The pharmacokinetics of perampanel are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures (in the absence of concomitant moderate or strong CYP3A4 inducers).

Absorption — Perampanel is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. Median time to reach peak concentration (t max) ranged from 0.5 to 2.5 hours under fasted condition. Co-administration of perampanel tablet with a high fat meal had no impact on the total exposure (AUC 0-inf) of perampanel and reduced the peak plasma concentration (C max) of perampanel by 11% to 40%. The t maxwas delayed by approximately 1 to 3 hours in fed state compared to that under fasted conditions.

Distribution — Data from in vitrostudies indicate that, in the concentration range of 20 ng/mL to 2000 ng/mL, perampanel is approximately 95 to 96% bound to plasma proteins, mainly bound to albumin and α1-acid glycoprotein. Blood to plasma ratio of perampanel is 0.55 to 0.59.

Metabolism — Perampanel is extensively metabolized via primary oxidation and sequential glucuronidation. Oxidative metabolism is primarily mediated by CYP3A4/5 and to a lesser extent by CYP1A2 and CYP2B6, based on results of in vitrostudies using recombinant human CYPs and human liver microsomes. Other CYP enzymes may also be involved.

Following administration of radiolabeled perampanel, unchanged perampanel accounted for 74% to 80% of total radioactivity in systemic circulation, whereas only trace amounts of individual perampanel metabolites were detected in plasma.

Elimination — Following administration of a radiolabeled perampanel tablet dose to 8 healthy elderly subjects, 22% of administered radioactivity was recovered in the urine and 48% in the feces. In urine and feces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. Population pharmacokinetic analysis of pooled data from 19 Phase 1 studies reported that t ½of perampanel was 105 hours on average. Apparent clearance of perampanel in healthy subjects and patients was approximately 12 mL/min.