The discovery and development of perampanel for the treatment of epilepsy

Abstract

Preclinical studies of perampanel have identified its broad-spectrum antiseizure effects in acute seizure models, with a narrow therapeutic index in the rotarod test similar to other AMPA receptor antagonists. This narrow therapeutic index is a potential problem for AMPA receptor antagonists. However, the discovery that perampanel has a very long half-life in humans, with gradual accumulation in plasma, could contribute to the development of tolerance. This, coupled with the identification of an optimal dosing strategy for individual patients, may help to maximize the utility of perampanel in the treatment of epilepsy.

Perampanel for epilepsy with partial-onset seizures: a pharmacokinetic and pharmacodynamic evaluation

“…PER suppressed seizures in acute models of generalized seizures (maximal electroshock and PTZ model in mice), and was efficacious against seizures with partial onset (audiogenic seizures in DBA/2 mice, 6 Hz seizure model in mice) [23]. In addition, PER showed effects in chronic models Box 1.…”

“…Whereas PER had a short half-life in several mammalian species [23], in humans PER is only second to Brome in elimination time. Clearance of PER was 10.9 ml/min in healthy volunteers and 12 ml/min in epilepsy patients [38][39][40].…”

“…To study their antiepileptic properties, AMPA receptor antagonists have been tested in a number of experimental epilepsy models [20,[22][23][24][25][26][27]. PER suppressed seizures in acute models of generalized seizures (maximal electroshock and PTZ model in mice), and was efficacious against seizures with partial onset (audiogenic seizures in DBA/2 mice, 6 Hz seizure model in mice) [23].…”

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

“…Up to now, perampanel is the first and only approved selective and non-competitive AMPA receptor antagonist. 20 In three phase III randomised, double-blind, placebo-controlled trials of add-on perampanel in patients (n=1,478) with refractory focal seizures, add-on perampanel in combination with one or more of the four most commonly co-administered AEDs (carbamazepine, valproic acid, lamotrigine, and levetiracetam), was efficient at reducing focal seizure frequency and improving responder rates compared with placebo, and was generally well tolerated. 21 In addition, some preclinical data suggest a supra-additive efficacy of the combination of perampanel with zonisamide in a chronic epilepsy rat model.…”

Current possibilities of treatment of generalized convulsive seizures

“…В июне 2015 г. перампанел был одобрен в США Управлением по контролю качества про-дуктов и лекарственных средств (FDA), в Европейском Союзе -соответствующей комиссией, а также в России в качестве дополнительной терапии первичных генерали-зованных тонико-клонических приступов у пациентов с эпилепсией в возрасте 12 лет и старше 1 . Перампанел (файкомпа) -первый одобренный для клинического применения ПЭП, подавляющий возбуж-дение постсинаптических мембран посредством селек-тивного ингибирования глутаматных рецепторов [8]. В отличие от многих традиционных ПЭП перампанел по-казал эффективность при широком спектре эксперимен-тальных моделей приступов [9].…”