title: Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes.
abstract: OBJECTIVE
  To further explore the impact of concomitant antiepileptic drugs (AEDs) on the efficacy and tolerability of adjunctive perampanel for focal epilepsy.
  
  
  METHODS
  Data were pooled from three phase III trials of adjunctive perampanel in patients (≥12 years of age) with refractory partial-onset seizures. Concomitant AEDs were categorized according to whether or not they were enzyme-inducing AEDs (EIAEDs; known to reduce perampanel plasma concentrations) or sodium channel blockers (SCBs). Post hoc analyses assessed the impact of co-administration of non-EIAED SCBs and the overall number of concomitant AEDs on changes in seizure frequency, 50% responder rates, rates of treatment-emergent adverse events (TEAEs), and rates of discontinuation due to TEAEs, in patients randomized to receive daily placebo or perampanel 2, 4, 8, or 12mg.
  
  
  RESULTS
  Amongst 1480 randomized and treated patients, most were receiving two or more concomitant AEDs (n=1273, 86.0%), one or more EIAEDs (n=1083, 73.2%), and/or one or more SCBs (n=1203, 81.3%) at Baseline. The magnitude of seizure reduction appeared unaffected by the presence of non-EIAED SCBs, but lower in the presence of multiple AEDs. Frequency of TEAEs did not appear to be affected by the presence of non-EIAED SCBs or multiple AEDs.
  
  
  CONCLUSIONS
  Beyond the known interactions between perampanel and EIAEDs, perampanel efficacy appears to be unaffected by the use of concomitant non-EIAED SCBs, but may be reduced in the presence of multiple concomitant AEDs (possibly indicative of the presence of more refractory epilepsy). Nonetheless, with careful titration to balance efficacy and tolerability, perampanel may be combined with a range of AEDs, facilitating integration into treatment plans.
authors.affiliation: Department of Medicine, The University of Melbourne, Melbourne, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, Australia; The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China. Electronic address: kwanp@unimelb.edu.au.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
authors.affiliation: Western Infirmary, Glasgow, UK. Electronic address: Martin.Brodie@glasgow.ac.uk.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Brodie
authors.affiliation: Eisai Neuroscience Product Creation Unit, Woodcliff Lake, NJ, USA. Electronic address: Antonio_Laurenza@eisai.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laurenza
authors.affiliation: Complete Medical Communications, Macclesfield, UK. Electronic address: hannah.fitzgibbon@complete-mc.com.
authors.forename: Hannah
authors.initials: H
authors.lastname: FitzGibbon
authors.affiliation: University of Wisconsin, Madison, WI, USA. Electronic address: barry.gidal@wisc.edu.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Gidal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011728:Pyridones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel
keywords: Antiepileptic drugs; Enzyme induction.; Partial-onset seizures; Perampanel; Sodium channel blockers