Perampanel: A novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy

Abstract

SUMMARYPurpose: To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial-onset seizures. ]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (K i 11.2 ± 0.8 nM) and GYKI52466 (K i 12.4 ± 1 lM). In mice, perampanel showed protective effects against audiogenic, MES-induced, and PTZ-induced seizures (ED 50 s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock-induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala-kindled rats, perampanel significantly increased afterdischarge threshold (p < 0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p < 0.05 for all measures vs. vehicle). Perampanel caused dosedependent motor impairment in both mice (TD 50 1.8 mg/ kg) and rats (TD 50 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD 50 in rotarod test/ ED 50 in seizure test) was 1.1, 3.8, and 1.9 for MES-induced, audiogenic, and PTZ-induced seizures, respectively. In rat, dog, and monkey, perampanel had a half-life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively. Significance: These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.

Review of clinical studies of perampanel in adolescent patients

“…In cultured rat cortical neurons, perampanel acts in a concentration‐dependent manner, with a 50% inhibitory concentration of 93 nM compared with 12.5  μ M for the noncompetitive AMPA receptor antagonist GYKI52466 (Hanada et al. 2011). AMPA receptor antagonists have a broad spectrum of anticonvulsant activity, being effective against fully kindled seizures (Rogawski 2011).…”

Satellite Symposium Abstract

“…1 Patients with uncontrolled disease can benefit from careful selection of combination drug therapy, and from ongoing adjustment to the AED regimen where needed. 2,3 Perampanel is a first-in-class selective AMPA receptor antagonist, 4 and has recently received a positive CHMP opinion for use as an adjunctive treatment for partial seizures. In this symposium, we will review the emergence of the AMPA receptor as a rational drug target, and discuss efficacy and safety/tolerability data from the phase 3 clinical trial programme for this novel AED.…”

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

“…Perampanel has shown anti-epileptic activity in different animal models of epilepsy (Table 1), binding even when glutamate levels are high owing to its non-competitive binding properties. 8 Example of the involvement of AMPA receptors: focal seizures associated with brain tumours Focal seizures with or without secondary generalisation, are the most common symptom of brain tumours; 9 30-50% of these patients present with seizures; and 10-30% develop seizures later. Symptomatic management is essentially the same as for focal seizures, on the assumption that a focal brain lesion is responsible.…”