Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist

Abstract

Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile; E2007] is a potent, selective, orally-active non-competitive AMPA receptor antagonist developed for the treatment of epilepsy. Perampanel has a 2,3’-bipyridin-6’-one core structure, distinguishing it chemically from other AMPA receptor antagonist classes. Studies in various physiological systems indicate that perampanel selectively inhibits AMPA receptor-mediated synaptic excitation without affecting NMDA receptor responses. Blocking of AMPA receptors occurs at an allosteric site that is distinct from the glutamate recognition site. Radioligand binding studies suggest that the blocking site coincides with that of the non-competitive antagonist GYKI 52466, believed to be on linker peptide segments of AMPA receptor subunits that transduce agonist binding into channel opening. As is typical for AMPA receptor antagonists, perampanel exhibits broad-spectrum anti-seizure activity in diverse animal seizure models. Perampanel has high oral bioavailability, dose-proportional kinetics, and undergoes oxidative metabolism, primarily via CYP3A4, followed by glucuronidation. The terminal half-life (t½) in humans is 105 h; however, in the presence of a strong CYP3A4 inducer (such as carbamazepine) the t½ can be reduced. In sum, perampanel is a selective, centrally-acting, negative allosteric modulator of AMPA receptors with good oral bioavailability and favorable pharmacokinetic properties.

Perampanel, an Antagonist of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors, for the Treatment of Epilepsy: Studies in Human Epileptic Brain and Nonepileptic Brain and in Rodent Models

“…Previous preclinical reports have documented efficacy for perampanel against seizures in rodents (Hanada et al, 2011;Rogawski and Hanada, 2013). In those studies, perampanel attenuated audiogenic, electroshock-induced, PTZ-induced seizures, 6 Hz-driven seizures, and amygdalakindled seizures in rodents (Hanada et al, 2011).…”

“…There are four different AMPA receptor subunits (GLK A1-4 ), and these subunits are broadly, albeit differentially, expressed in the brain. The subunit selectivity of perampanel among AMPA receptor isoforms is not known (Rogawski and Hanada, 2013). Because perampanel causes both beneficial and adverse effects, we presume that perampanel inhibits AMPA receptors broadly across the brain, regardless of their subunit composition.…”

“…Perampanel has demonstrated efficacy in multiple preclinical models, which has helped inform drug development for epilepsy (Hanada et al, 2011;Hibi et al, 2012;Rogawski and Hanada, 2013). Perampanel has been investigated in several phase III clinical studies Krauss et al, 2012Krauss et al, , 2013Rektor et al, 2012).…”

Reflections on the Use of Perampanel in Epilepsy – Lessons from the Clinic and Real-world Evidence

“…40 A review of the pooled phase III data on the safety profile of perampanel in patients (age 12 and older) with focal epilepsy with or without secondary generalisation has revealed a relatively low incidence of serious treatment-emergent AEs (5.5%), particularly at low doses, and the majority of treatment-emergent AEs were mild or moderate in intensity. 41 Common neurological AEs associated with perampanel include dizziness, somnolence, ataxia, dysarthria, balance disorder and irritability.…”

“…1 As previously mentioned, perampanel therapeutic doses have been calculated to only inhibit a fraction of AMPA receptors. 40 Further, perampanel has a half-life of approximately 105 hours so that even after abrupt treatment discontinuation, blood levels fall gradually.…”