Meta-analysis of the efficacy and safety of perampanel in the treatment of epilepsy

Abstract

Background: Epilepsy is usually controlled, but not cured, with medication. However, over 30% of people with epilepsy do not have seizure control even with the best available medications. A new antiepileptic drug as adjunctive therapy for patients with partial onset seizures has been discovered. Perampanel (E2007) is an orally active, noncompetitive, and highly selective AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptor antagonist. AMPA receptor antagonist is a potential pharmacologic treatment for partial onset seizures by blocking excessive neuronal materials activation.[1] Perampanel was well tolerated and displayed favorable pharmacologic properties, including oral bioavailability and a long half-life in Phase I studies[2]. Perampanel has not been shown to interact with other ionotropic glutamate receptors and is without the behavioral phencyclidine-like adverse events that may be observed with some NMDA-receptors antagonists[3].

Objective: The aim of the meta-analysis is to demonstrate the magnitude of safety and efficacy of perampanel in treating the refractory partial onset seizures when compared to placebo.

Methods: A systematic review of Randomized controlled trials (RCTs) of perampanel was conducted. An electronic literature was identified by searching Medline, Embase and the Cochrane database. The primary efficacy end points were the 50% responder rate and treatment emergent adverse effects (TEAS). The secondary efficacy end points were the percent change in seizure frequency per 28 days relative to pre-perampanel baseline and incidence of withdrawal. In order to compare perampanel and placebo, we used Revmen to calculate Odds Ratio (OR), Confidence intervals, Risk Ratio (RR) and Risk Differences (RD).

Results: A total of five RCTs were included in the studies. During Phase II studies (labeled as studies 206[4] and 208[4]) 201 patients were involved. During Phase III studies (labeled as 304[1], 305[3] and 306[5]) 1331 patients were included. For 50% responder rate, the pooled odds ratio of 4mg, 8mg and 12mg perampanel compared with placebo was 1.76 [95%CI:1.15, 2.69], 2.26[95%CI:1.66, 3.08] and 2.11[95%CI:1.35, 3.32] respectively. The pooled odds ratio of perampanel for adverse events: headache 1.03 [95%CI : 0.79, 1.34] ; dizziness 3.48 [95%CI: 1.94, 6.24] ; somnolence 2.09 [95%CI: 1.39, 3.15] and fatigue 1.83 [95%CI: 1.23, 2.71] respectively.

Conclusion: The pooled odds ratio suggested perampanel might be more effective than placebo comparing the 50% responder rate. However, the risks of the TEAs were higher in the perampanel group when comparing with the placebo group. The use of 12 mg perampanel was shown be highly related with dizziness and somnolence.