title: Tolerability and safety of perampanel: two randomized dose-escalation studies.
abstract: OBJECTIVE
  To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non-competitive AMPA antagonist, as adjunctive therapy for refractory partial-onset seizures.
  
  
  METHODS
  Two consecutive, randomized, double-blind, dose-escalation studies recruited adults (18-70 years) with uncontrolled partial-onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8-week dose-titration, 4-week dose-maintenance) with placebo or perampanel (up to 4 mg/day, dosed once- or twice-daily). In study 208, patients received placebo or perampanel once-daily (up to 12 mg) for 16 weeks (12-week titration, 4-week maintenance).
  
  
  RESULTS
  Overall, 153 patients were randomized into study 206 (perampanel twice-daily, n = 51; perampanel once-daily, n = 51; placebo, n = 51). Study 208 included 48 patients (perampanel once-daily, n = 38; placebo, n = 10). The highest dose in study 206 - 4 mg/day - was well tolerated, with similar proportions of patients tolerating once-daily (82.4%) and twice-daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ≥ 6 mg perampanel once-daily in a Kaplan-Meier analysis. In both studies, the most common adverse events were CNS-related; most were of mild/moderate severity.
  
  
  CONCLUSIONS
  Perampanel was well tolerated across doses of 4-12 mg/day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.
authors: Johns Hopkins Hospital, Baltimore, MD 21287, USA. gkrauss@jhmi.edu
authors: G L
authors: GL
authors: Krauss
authors: M
authors: M
authors: Bar
authors: V
authors: V
authors: Biton
authors: J A
authors: JA
authors: Klapper
authors: I
authors: I
authors: Rektor
authors: N
authors: N
authors: Vaiciene-Magistris
authors: D
authors: D
authors: Squillacote
authors: D
authors: D
authors: Kumar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel