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

European Neurological Review, 2017;12(1):17–23 DOI: https://doi.org/10.17925/ENR.2017.12.01.17

Abstract:

Optimal 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 Carreňo 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.

Received: March 02, 2017 Accepted March 04, 2017
Correspondence: Mar Carreňo, 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.
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.

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 noncompetitive 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.

Rational treatment selection
A good understanding of AED mechanisms of action (MOAs) may facilitate decision-making on the most appropriate AED or AED combination for an individual patient.

Role of the AMPA receptor in epilepsy and the mode of action of perampanel
Targeting the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors for treatment of patients with epilepsy has generated considerable interest over the past few decades. An epileptic seizure is characterised by sudden disruption of the brain’s normal electrical activity. Neurotransmitters are released when action potentials arrive at the pre-synaptic neuron,2 opening voltage-gated calcium ions channels and allowing calcium ion influx. Calcium ions trigger exocytosis, releasing transmitter from vesicles into the synapse. Transmitter molecules bind to post-synaptic receptors, activating them and generating excitatory post-synaptic potentials (EPSPs). If sufficient EPSPs are triggered, the post-synaptic neuron is activated and action potentials occur. Synchronous EPSPs in groups of neighbouring neurons are responsible for epileptic field potentials.3

Glutamate is the principal excitatory neurotransmitter in the brain and glutamate-mediated excitatory neurotransmission is known to be critical in the pathophysiology of epilepsy.3,4 There are three families of glutamatergic ionotropic receptors with intrinsic cation permeable channels (N-methyl-D-aspartate [NMDA], AMPA and kainate).5 Glutamate, via the AMPA receptor, drives fast synaptic excitation at individual synapses, and across networks, whereas NMDA receptors are involved in synaptic plasticity and long-term potentiation induction. AMPA receptor antagonists, in contrast to NMDA receptor antagonists, are not known to impact synaptic plasticity, long-term potentiation and memory.2

The AMPA receptor is the predominant mediator of excitatory neurotransmission in the central nervous system (CNS). These receptors are mainly located post-synaptically and are critical to the generation and spread of epileptic activity.2 There are several lines of evidence to support the key role of the AMPA receptor in epilepsy. In early development, calcium-permeable AMPA receptors prevail and can be involved in increasing cellular calcium ion concentrations and subsequently neurotoxicity in animal models of epilepsy.6 AMPA and NMDA receptors play different roles during epileptiform activity in vitro.7 Blocking NMDA receptors does not eliminate the epileptiform bursting – the later bursts are inhibited but the discharge can still be triggered. By contrast, blocking AMPA receptors eliminates the epileptiform activity altogether. 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.10 Seizures associated with primary brain tumours are difficult to treat and often drug resistant; in a large cohort study, complete seizure control was achieved in 20 of 158 (12.6%) patients with a brain tumour.11

Impaired glutamate homeostasis in and around tumours is central to seizure generation.12 Gliomas release glutamate, which has been shown to induce epileptiform activity in mice.13 Moreover, in human glioma samples, peri-tumoural glutamate levels correlate with post-operative seizure recurrence.14 AEDs targeting the glutamate system may therefore have potential for seizure management. Electrophysiological recordings in brain slices from nine adults who underwent glioma resection showed spontaneous inter-ictal discharges; perampanel reduced the frequency of discharges, and eliminated them at higher concentrations.15 Further, the power of elicited ictal events was significantly reduced by perampanel. Perampanel is a treatment option for focal seizures associated with brain tumours; its efficacy in this setting has been demonstrated in case studies (Rosche et al.16 and data not shown) although in phase III studies of add-on perampanel in focal seizures, patients with progressive CNS tumours were excluded.

Rational polytherapy
Within the concept of ‘rational polytherapy’ it is thought that combining AEDs with different MOAs should be more effective than combining treatments based on the same mechanism. In theory, this approach covers multiple targets without risking additive adverse events (AEs).17 Indeed, in a real-world setting (n=8,615), AED combinations with different MOAs were associated with greater treatment persistence (measured as the number of days from the index AED combination date to the end of the index combination, the end of enrolment, or the end of available data [31 March 2011], whichever occurred first) than using combinations with the same MOAs.18

Sodium channel blockade has been recognised as a major anticonvulsant mechanism in epilepsy.19 The majority of available AEDs mainly exert their effects through modulation of sodium or calcium channels, direct modulation of synaptic release, or enhancement of gamma-aminobutyric acid (GABA)-related mechanisms. 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.22 Zonisamide modulates GABA-mediated neuronal inhibition, voltage-sensitive sodium channels and T-type calcium currents, thereby disrupting synchronised neuronal

firing, reducing the spread of seizure discharges and disrupting subsequent epileptic activity.23

The MOA of perampanel supports its use for anti-epilepsy treatment as part of rational polytherapy. However, data supporting the premise of combining drugs with different MOAs are limited to the valproic acid and lamotrigine combination24 and further investigation into this area is warranted. The concept of rational therapy remains therefore unproven as yet.

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Keywords: AMPA receptor, anti-epileptic drugs (AEDs), real-world data, cognitive impairment, psychiatric comorbidity