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Review Epilepsy Reflections on the Use of Perampanel in Epilepsy – Lessons from the Clinic and Real-world Evidence Eugen Trinka 1 and Mar Carrenˇo 2 1. Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University and Centre for Cognitive Neuroscience, Salzburg, Austria; 2. Epilepsy Unit, Hospital Clinic, Barcelona, Spain O ptimal epilepsy management includes five important elements: rational treatment selection, efficacy, off-target effects, adherence and interactions and dosing issues. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl]benzonitrile; E2007) is the first potent, selective, orally-active non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist approved for the treatment of patients with epilepsy. Results from randomised controlled trials and real-world studies of refractory epilepsy populations treated with perampanel showed effective frequency reduction for both focal-onset seizures (without and with secondary generalisation) and for primary generalised tonic-clonic seizures. Perampanel therapeutic doses have been calculated to only inhibit a fraction of AMPA receptors, thereby to enable sufficient seizure control without substantial impairment of neurological function. Further investigation in special subpopulations of people with epilepsy, including the elderly and people with learning disability or psychiatric comorbidities, is warranted. With an average long half-life of 105 hours, perampanel may be more forgiving in circumstances of suboptimal adherence. Perampanel is not a strong inducer or inhibitor of cytochrome P450 enzymes, and dose adjustment is not always required for the elderly or for those with mild renal impairment. Keywords AMPA receptor, anti-epileptic drugs (AEDs), real-world data, cognitive impairment, psychiatric comorbidity Disclosure: Professor Eugen Trinka is a paid consultant for UCB, Eisai, Bial, Medtronic, EVER Neuro Pharma, Biogen-Idec, Sanofi-Genzyme, Shire, Marinus, Takeda, Newbridge and Sunovion. Professor Trinka has received research funding (directly, or to institution) from GlaxoSmithKline, Biogen-Idec, Eisai, Novartis, Red Bull, Bayer, and UCB Pharma Ltd, and speaker’s honoraria from GlaxoSmithKline, Boehringer Ingelheim, Eisai, Bial, UCB Pharma Ltd, Sanofi-Genzyme, Shire and Sanofi-Aventis. He is the chief executive officer of Neuroconsult GmbH and has been awarded grants from the Austrian Science Fund (FWF), Österreichische Nationalbank, European Union. Dr Mar Carrenˇo has received advisory board or speaker’s honoraria from Shire, Bial, Eisai, Esteve, and UCB Pharma Ltd and has received research grants from Bial and Eisai. There were no publication fees associated with the publication of this article. Acknowledgments: Medical writing support, including preparation of the drafts under the guidance of the authors, was provided by Catherine Amey, Touch Medical Media. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 2 March 2017 Accepted: 4 March 2017 Citation: European Neurological Review, 2017;12(1):17–23 Corresponding Author: Mar Carrenˇ o, Department of Neurology, Hospital Clínic. c/Villarroel 170, 08036, Barcelona, Spain. E: mcarreno@clinic.cat Support: The publication of this article was supported by Eisai. The views and opinions expressed in the article are those of the authors and not necessarily those of Eisai. TOU CH MED ICA L MEDIA As the armamentarium of anti-epileptic drugs (AEDs) continues to expand, epilepsy management is becoming increasingly complex. This necessitates multiple considerations for the choice of the most appropriate AED that can broadly be organised into five categories: (i) rational treatment selection (taking into account mode of action of AEDs); (ii) efficacy with respect to seizure control according to the patient’s expectations and needs (and taking into account the seizure type(s) and syndromes); (iii) off-target effects, whereby an AED interacts with a system other than that for which it is intended (may be beneficial, for example, facilitating sleep, or harmful such as inducing dyskinesias); (iv) adherence concerns, which may involve taking into account drug characteristics, including pharmacokinetics and administration; and (v) interactions and dosing. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile; E2007) is the first potent, selective, orally-active non- competitive AMPA receptor antagonist approved for treatment of patients with epilepsy. Perampanel is indicated as an adjunctive therapy for the treatment of patients with focal-onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years or older. More recently, the European Commission approved an indication expansion for the adjunctive treatment for primary generalised tonic-clonic (PGTC) seizures in patients with idiopathic generalised epilepsy (IGE) who are at least 12 years of age. 1 This review will examine these five considerations for epilepsy management as a treatment selection framework and will explore to what extent perampanel fulfils these requirements. For this purpose, the work is based on three symposia, initiated and funded by Eisai Europe, Ltd, and held at the European Congress on Epileptology (ECE), which took place in Prague, Czech Republic from 11–15 September 2016. 17