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CNS Drugs

, Volume 26, Issue 12, pp 1085–1096 | Cite as

Perampanel

As Adjunctive Therapy in Patients with Partial-Onset Seizures
  • Greg L. PloskerEmail author
Adis Drug Profile

Abstract

Perampanel is a novel antiepileptic drug (AED) used as adjunctive therapy in adolescents and adults with partial-onset seizures (with or without secondarily generalized seizures). It is a selective, noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors on post-synaptic neurons, and is the first in this new class of AED known as AMPA receptor antagonists. In three randomized, double-blind, placebo-controlled, phase III trials in adolescent and adult patients with refractory partial-onset seizures, once-daily administration of perampanel 4, 8 and 12 mg/day (6-week titration phase followed by 13-week maintenance phase), as adjunctive therapy with one to three AEDs, was statistically superior to adjunctive placebo in achieving the key efficacy endpoints of the median percentage change from baseline in seizure frequency and/or the proportion of patients with a ≥50 % reduction in seizure frequency relative to baseline. Adverse events were usually mild or moderate in severity and the most frequent treatment-emergent events reported among perampanel recipients were CNS-related, such as dizziness, somnolence, headache and fatigue. Interim data from a large extension study (16-week blinded conversion period followed by open-label maintenance phase), which enrolled patients who completed the phase III trials, showed a similar group response for the reduction in seizure frequency over at least 1 year of adjunctive treatment with perampanel. Perampanel was generally well tolerated over the longer-term in extension studies, with no unexpected adverse events reported. On the basis of its overall clinical profile and unique mechanism of action, perampanel is a useful adjunctive treatment option in patients with refractory partial-onset seizures.

Keywords

Seizure Frequency Oxcarbazepine Responder Rate Perampanel AMPA Receptor Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes based on any comments received were made by the author on the basis of scientific and editorial merit.

References

  1. 1.
    Neligan A, Hauser WA, Sander JW. The epidemiology of the epilepsies. Handb Clin Neurol. 2012;107(3rd series):113–33.Google Scholar
  2. 2.
    Figueroa Garcia A. Partial epilepsies. 2012. http://emedicine.medscape.com/article/1186635-overview. Accessed 2012 Sep 17 2012.
  3. 3.
    Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676–85.PubMedCrossRefGoogle Scholar
  4. 4.
    The National Society for Epilepsy. Epilepsy: an introduction to epileptic seizures. 2012. http://www.epilepsysociety.org.uk/AboutEpilepsy/Whatisepilepsy/Seizures. Accessed 17 Sep 2012.
  5. 5.
    Perucca E. The pharmacology of new antiepileptic drugs: does a novel mechanism of action really matter? CNS Drugs. 2011;25(11):907–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs. 2011;25(2):89–107.PubMedCrossRefGoogle Scholar
  7. 7.
    Kwan P, Schachter SC, Brodie MJ. Current concepts: drug-resistant epilepsy. N Engl J Med. 2011;365(10):919–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry. 2004;75(10):1376–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Elliott JO, Lu B, Shneker B, et al. Comorbidity, health screening, and quality of life among persons with a history of epilepsy. Epilepsy Behav. 2009;14(1):125–9.PubMedCrossRefGoogle Scholar
  10. 10.
    European Medicines Agency. Fycompa (perampanel) film-coated tablet: summary of product characteristics. 2012. http://www.ema.europa.eu/docs. Accessed 2012 Sept 6.
  11. 11.
    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(7):1331–40.PubMedCrossRefGoogle Scholar
  12. 12.
    Scharfman HE. The neurobiology of epilepsy. Curr Neurol Neurosci Rep. 2007;7(4):348–54.PubMedCrossRefGoogle Scholar
  13. 13.
    During MJ, Spencer DD. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet. 1993;341(8861):1607–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics. 2007;4(1):18–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr. 2000;130(4S Suppl):1007S–15S.Google Scholar
  16. 16.
    Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011;11(2):56–63.PubMedCrossRefGoogle Scholar
  17. 17.
    Ceolin L, Bortolotto ZA, Bannister N, et al. A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus. Neurochem Int. 2012;61(4):517–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Hussein Z, Ferry J, Krauss G, et al. Demographic factors and concomitant antiepileptic drugs have no effect on the pharmacodynamics of perampanel [abstract no. P06.127]. 64th Annual Meeting of the American Academy of Neurology, New Orleans (LA); 21–28 Apr 2012.Google Scholar
  19. 19.
    Hussein Z, Critchley D, Ferry J, et al. Population pharmacokinetics of perampanel, a selective, noncompetitive AMPA receptor antagonist, in patients with refractory partial-onset seizures participating in a randomized, double-blind, placebo-controlled phase III study [abstract no. p821]. Epilepsia. 2011;52(Suppl. 6):248–9.Google Scholar
  20. 20.
    Fycompa (perampanel) US prescribing information. 2012. http://us.eisai.com/package_inserts/FycompaPI.pdf. Accessed Oct 24 2012.
  21. 21.
    Templeton D. Pharmacokinetics of perampanel, a highly selective ampa-type glutamate receptor antagonist [abstract no. 1.199]. 63rd Annual Meeting of the American Epilepsy Society, Boston (MA); 4–8 Dec 2009.Google Scholar
  22. 22.
    Laurenza A, Ferry J, Hussein Z. Population pharmacokinetics and pharmacodynamics of perampanel: a pooled analysis from three phase III trials [abstract no. 2.231 plus poster]. 65th Annual Meeting of the American Epilepsy Society, Baltimore (MD); 2–6 Dec 2011.Google Scholar
  23. 23.
    French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79(6):589–96.PubMedCrossRefGoogle Scholar
  24. 24.
    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 Epub. 2012 Aug 22.Google Scholar
  25. 25.
    Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78(18):1408–15.PubMedCrossRefGoogle Scholar
  26. 26.
    Krauss GL, Bar M, Biton V, et al. Tolerability and safety of perampanel: two randomized dose-escalation studies. Acta Neurol Scand. 2012;125(1):8–15.PubMedCrossRefGoogle Scholar
  27. 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 Epub. 2012 Aug 22.Google Scholar
  28. 28.
    Ben-Menachem E, Krauss GL, Noachtar S, et al. Efficacy and safety of once-daily adjunctive perampanel, a selective AMPA antagonist: a pooled analysis of three phase III trials in patients with treatment-resistant partial-onset seizures [abstract no. p656]. Epilepsia. 2012;53(Suppl. 5):190–1.Google Scholar
  29. 29.
    Krauss G, Perucca E, Brodie M, et al. Pooled analysis of responder rates and seizure freedom from phase III clinical trials of adjunctive perampanel, a selective, non-competitive AMPA receptor antagonist [abstract no. PD3.010]. 64th Annual Meeting of the American Academy of Neurology, New Orleans (LA); 21–28 April 2012.Google Scholar
  30. 30.
    Steinhoff BJ, Gauffin H, Mckee P, et al. Efficacy of perampanel, a selective AMPA antagonist, in complex partial and secondarily generalized seizures: a pooled analysis of phase III studies in patients with treatment-resistant partial-onset seizures [abstract no. p417]. Epilepsia. 2012;53(Suppl. 5):122.Google Scholar
  31. 31.
    Kramer L, Perucca E, Ben-Menachem E, et al. Perampanel, a selective, non-competitive AMPA receptor antagonist as adjunctive therapy in patients with refractory partial-onset seizures: a dose response analysis from phase III studies [abstract no. P06.117]. 64th Annual Meeting of the American Academy of Neurology, New Orleans (LA); 21–28 Apr 2012.Google Scholar
  32. 32.
    Trinka E, Straub H, Squillacote D, et al. Analysis of seizure frequency reduction by concomitant antiepileptic drug (AED) use with adjunctive perampanel: pooled phase III results [abstract no. p669]. Epilepsia. 2012;53(Suppl. 5):194–5.Google Scholar
  33. 33.
    Laurenza A, French J, Gil-Nagel A, et al. Perampanel, a selective, non-competitive AMPA receptor antagonist, prolongs time to seizure recurrence in patients with epilepsy: results of pooled phase III clinical trial data [abstract no. S56.005]. 64th Annual Meeting of the American Academy of Neurology, New Orleans (LA); 21–28 Apr 2012.Google Scholar
  34. 34.
    Villanueva V, Rozentals G, Yang H, et al. Efficacy and safety of perampanel as adjunctive therapy in adolescents with refractory partial-onset seizures: analysis of a randomized, double-blind, placebocontrolled phase III study [abstract no. p799]. Epilepsia. 2011;52(Suppl. 6):242.Google Scholar
  35. 35.
    Krauss GL, Kerling F, Villanueva V, et al. Drug resistance and seizure severity of patients in partial-onset seizure registration trials of perampanel compared with recently approved antiepileptic drugs [abstract no. p176]. Epilepsia. 2012;53(Suppl. 5):52–3.Google Scholar
  36. 36.
    Rektor I, Krauss GL, Bar M, et al. Perampanel Study 207: long-term open-label evaluation in patients with epilepsy. Acta Neurol Scand. 2012;126(4):263–9.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  1. 1.AdisAucklandNew Zealand

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