title: The discovery and development of perampanel for the treatment of epilepsy.
abstract: BACKGROUND
  Perampanel is a novel AMPA receptor antagonist, approved in over 35 countries as an adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older (18 years and older in Canada). These countries include the members of the European Union, the USA, Canada and Switzerland. The AMPA receptor antagonist, perampanel, is the first approved antiepileptic drug to inhibit excitation of postsynaptic membranes through the selective inhibition of glutamate receptors.
  
  
  METHODS
  This drug discovery case history focuses on the discovery and profiling of perampanel. It analyzes the pharmacological, behavioral and molecular mechanisms of perampanel and how they contribute to the therapeutic benefits of the drug. The article is based on the data reported in published preclinical and clinical studies, product labels and poster presentations.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Eisai Co., Ltd, Japan/Asia Clinical Research Product Creation Unit , Koishikawa 4-6-10, Bunkyo-ku, Tokyo 112-8088 , Japan +81 3 3817 5235 ; +81 3 3815 7539 ; t-hanada@hhc.eisai.co.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hanada
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D009570:Nitriles; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D018091:Receptors, AMPA; C551441:perampanel