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:


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:
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.

1. Eisai Ltd, Fycompa, Summary of product characteristics, Available from: medicine/26951 (accessed 20 April 2017).
2. Rogawski MA, Revisiting AMPA receptors as an antiepileptic drug target, Epilepsy Curr, 2011;11:56–63.
3. Rogawski MA, AMPA receptors as a molecular target in epilepsy therapy, Acta Neurol Scand Suppl, 2013:9–18.
4. Barker-Haliski M, White HS, Glutamatergic mechanisms associated with seizures and epilepsy, Cold Spring Harb Perspect Med, 2015;5:a022863.
5.Meldrum BS, Glutamate as a neurotransmitter in the brain: review of physiology and pathology, J Nutr, 2000;130(4S Suppl):1007s–15s.
6. Dohare P, Zia MT, Ahmed E, et al., AMPA-Kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage, J Neurosci, 2016;36:3363–77.
7. Traub RD, Miles R, Jefferys JG, Synaptic and intrinsic conductances shape picrotoxin-induced synchronized afterdischarges in the guinea-pig hippocampal slice, J Physiol, 1993;461:525–47.
8. Hanada T, Hashizume Y, Tokuhara N, et al., Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy, Epilepsia, 2011;52:1331–40.
9. van Breemen MS, Wilms EB, Vecht CJ, Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management, Lancet Neurol, 2007;6:421–30.
10. Huberfeld G, Vecht CJ, Seizures and gliomas-towards a single therapeutic approach, Nat Rev Neurol, 2016;12:204–16.
11. Hildebrand J, Lecaille C, Perennes J, Delattre JY, Epileptic seizures during follow-up of patients treated for primary brain tumors, Neurology, 2005;65:212–5.
12. Pallud J, Capelle L, Huberfeld G, Tumoral epileptogenicity: how does it happen?, Epilepsia, 2013;54 Suppl 9:30–4.
13. Buckingham SC, Campbell SL, Haas BR, et al., Glutamate release by primary brain tumors induces epileptic activity, Nat Med, 2011;17:1269–74.
14. Neal A, Yuen T, Bjorksten AR, et al., Peritumoural glutamate correlates with post-operative seizures in supratentorial gliomas, J Neurooncol>, 2016;129:259–67.
15. Cunningham M. Targeting elevated glutamate in brain tumour related epilepsy. Presented at: 12th European Congress on Epileptology (ECE), Prague, Czech Republic, 11–15 September 2016.
16. Rosche J, Piek J, Hildebrandt G, et al., Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and without MGMT promotor methylation [Article in German], Fortschr Neurol Psychiatr, 2015;83:286–9.
17. Brodie MJ, Sills GJ, Combining antiepileptic drugs-rational polytherapy?, Seizure, 2011;20:369–75.
18. Margolis JM, Chu BC, Wang ZJ, et al., Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action, JAMA Neurology, 2014;71:985–93.
19. Meldrum BS, Rogawski MA, Molecular targets for antiepileptic drug development, Neurotherapeutics, 2007;4:18–61.
20. Hanada T, The discovery and development of perampanel for the treatment of epilepsy, Expert Opin Drug Discov, 2014;9:449–58.
21. Steinhoff BJ, Ben-Menachem E, Ryvlin P, et al., Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies, Epilepsia, 2013;54:1481–9.
22. Russmann V, Salvamoser JD, Rettenbeck ML, et al., Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy, Epilepsia, 2016;57:638–47.
23. Eisai Ltd, Zonegran, Summary of product characteristics, Available from: document_library/EPAR_-_Product_Information/human/000577/ WC500052431.pdf (accessed 11 November 2016).
24. Moeller JJ, Rahey SR, Sadler RM, Lamotrigine-valproic acid combination therapy for medically refractory epilepsy, Epilepsia, 2009;50:475–9.
25. French JA, Krauss GL, Biton V, et al., Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304, Neurology, 2012;79:589–96.
26. French JA, Krauss GL, Steinhoff BJ, et al., Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305, Epilepsia, 2013;54:117–25.
27. Krauss GL, Perucca E, Ben-Menachem E, et al. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307, Epilepsia, 2013;54:126–34.
28. French JA, Krauss GL, Wechsler RT, et al., Perampanel for tonicclonic seizures in idiopathic generalized epilepsy A randomized trial, Neurology, 2015;85:950–7.
29. Wechsler R, French J, Trinka E, et al., Long-term safety and efficacy of adjunctive perampanel in patients with drug-resistant primary generalised tonic-clonic seizures in idiopathic generalised epilepsy: results of an open-label extension. Presented at: 12th European Congress on Epileptology (ECE), Prague, Czech Republic, 11–15 September 2016. Abstract 555.
30. Tlusta E, Handoko KB, Majoie M, et al., Clinical relevance of patients with epilepsy included in clinical trials, Epilepsia, 2008;49:1479–80.
31. Ben-Menachem E, Data from regulatory studies: What do they tell? What don’t they tell?, Acta Neurol Scand Suppl, 2005;181:21–5.
32. Trinka EZ, Zimmermann G, Rohracher A, et al., A. Pan-European real-world experience with perampanel: rationale, design, and preliminary data from pooled observational studies across the continent. Presented at: 12th European Congress on Epileptology (ECE), Czech Republic, 11–15 September 2016. Abstract P756.
33. Trinka E, Steinhoff BJ, Nikanorova M, Brodie MJ, Perampanel for focal epilepsy: insights from early clinical experience, Acta Neurol Scand, 2016;133:160–72.
34. Singh K, Shah YD, Luciano D, et al., Safety and efficacy of perampanel in children and adults with various epilepsy syndromes: A single-center postmarketing study, Epilepsy Behav, 2016;61:41–5.
35. Doran Z, Shankar R, Keezer MR, et al., Managing anti-epileptic drug treatment in adult patients with intellectual disability: a serious conundrum, Eur J Neurol, 2016;23:1152–7.
36. Kanner AM, Management of psychiatric and neurological comorbidities in epilepsy, Nat Rev Neurol, 2016;12:106–16.
37. Maurousset A, Limousin N, Praline J, et al., Adjunctive perampanel in refractory epilepsy: Experience at tertiary epilepsy care center in Tours, Epilepsy Behav, 2016;61:237–41.
38. French JA, Staley BA, AED treatment through different ages: as our brains change, should our drug choices also?, Epilepsy Curr, 2012;12(Suppl 3):22–7.
39. Villanueva V, Garces M, Lopez-Gonzalez FJ, et al., Safety, efficacy and outcome-related factors of perampanel over 12 months in a real-world setting: The FYDATA study,Epilepsy Res, 2016;126:201–10.
40. Rogawski MA, Hanada T, Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist, Acta Neurol Scand Suppl, 2013:19–24.
41. Rugg-Gunn F, Adverse effects and safety profile of perampanel: a review of pooled data, Epilepsia, 2014;55 Suppl 1:13–5.
42. Lin JJ, Mula M, Hermann BP, Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan, Lancet, 2012;380:1180–92.
43. Ettinger AB, Reed ML, Goldberg JF, Hirschfeld RM, Prevalence of bipolar symptoms in epilepsy vs other chronic health disorders, Neurology, 2005;65:535–40.
44. Kanner AM, Schachter SC, Barry JJ, et al., Depression and epilepsy: epidemiologic and neurobiologic perspectives that may explain their high comorbid occurrence,Epilepsy Behav, 2012;24:156–68.
45. Ettinger AB, Ottman R, Lipton RB, et al., Attention-deficit/ hyperactivity disorder symptoms in adults with self-reported epilepsy: Results from a national epidemiologic survey of epilepsy, Epilepsia, 2015;56:218–24.
46. Brandt C, Schoendienst M, Trentowska M, et al., Prevalence of anxiety disorders in patients with refractory focal epilepsy-a prospective clinic based survey, Epilepsy Behav, 2010;17:259–63.
47. Adams SJ, O’Brien TJ, Lloyd J, et al., Neuropsychiatric morbidity in focal epilepsy, Br J Psychiatry, 2008;192:464–9.
48. Dalmagro CL, Velasco TR, Bianchin MM, et al., Psychiatric comorbidity in refractory focal epilepsy: a study of 490 patients, Epilepsy Behav, 2012;25:593–7.
49. Glosser G, Zwil AS, Glosser DS, et al., Psychiatric aspects of temporal lobe epilepsy before and after anterior temporal lobectomy, J Neurol Neurosurg Psychiatry, 2000;68:53–8.
50. Piedad J, Rickards H, Besag FM, Cavanna AE, Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations, CNS Drugs, 2012;26:319–35.
51. Brodie MJ, Besag F, Ettinger AB, et al., Epilepsy, antiepileptic drugs, and aggression: an evidence-based review, Pharmacol Rev, 2016;68:563–602.
52. Eisai Ltd, Fycompa, US prescribing information, Available from: label/2016/208277s000lbl.pdf (accessed 29 March 2017).
53. Mula M, Trimble MR, Lhatoo SD, Sander JW, Topiramate and psychiatric adverse events in patients with epilepsy, Epilepsia, 2003;44:659–63.
54. Helmstaedter C, Mihov Y, Toliat MR, et al., Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam, Epilepsia, 2013;54:36–44.
55. Witt JA, Helmstaedter C, Monitoring the cognitive effects of antiepileptic pharmacotherapy-approaching the individual patient, Epilepsy Behav, 2013;26:450–6.
56. Witt JA, Helmstaedter C, Should cognition be screened in newonset epilepsies? A study in 247 untreated patients, J Neurol, 2012;259:1727–31.
57. Witt JA, Elger CE, Helmstaedter C, Adverse cognitive effects of antiepileptic pharmacotherapy: Each additional drug matters, Eur Neuropsychopharmacol, 2015;25:1954–9.
58. Boshuisen K, van Schooneveld MM, Uiterwaal CS, et al., Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery, Ann Neurol, 2015;78:104–14.
59. Skirrow C, Cross JH, Cormack F, et al., Long-term intellectual outcome after temporal lobe surgery in childhood, Neurology, 2011;76:1330–7.
60. Helmstaedter C, Elger CE, Witt JA, The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery, Seizure, 2016;36:63–9.
61. Meador KJ, Yang H, Pina-Garza JE, et al., Cognitive effects of adjunctive perampanel for partial-onset seizures: A randomized trial, Epilepsia, 2016;57:243–51.
62. Helmstaedter C, Witt JA, The effects of levetiracetam on cognition: a non-interventional surveillance study, Epilepsy Behav, 2008;13:642–9.
63. Faught RE, Weiner JR, Guerin A, et al., Impact of nonadherence to antiepileptic drugs on health care utilization and costs: findings from the RANSOM study, Epilepsia, 2009;50:501–9.
64. Faught E, Adherence to antiepilepsy drug therapy, Epilepsy Behav, 2012;25:297–302.
65. Cramer JA, Glassman M, Rienzi V, The relationship between poor medication compliance and seizures, Epilepsy Behav, 2002;3:338–42.
66. Claxton AJ, Cramer J, Pierce C, A systematic review of the associations between dose regimens and medication compliance, Clin Ther, 2001;23:1296–310.
67. Eatock J, Baker GA, Managing patient adherence and quality of life in epilepsy, Neuropsychiatr Dis Treat, 2007;3:117–31.
68. Brodie MJ, Mintzer S, Pack AM, et al., Enzyme induction with antiepileptic drugs: cause for concern?, Epilepsia, 2013;54:11–27.
Keywords: AMPA receptor, anti-epileptic drugs (AEDs), real-world data, cognitive impairment, psychiatric comorbidity