title: The effects of ethanol on the pharmacokinetics, pharmacodynamics, safety, and tolerability of ezogabine (retigabine).
abstract: BACKGROUND
  The antiepileptic drug ezogabine (EZG; US adopted name for retigabine [the international nonproprietary name]) reduces neuronal excitability by enhancing potassium channel activity. EZG has been approved as adjunctive treatment for adults with partial-onset seizures.
  
  
  OBJECTIVE
  The goal of this study was to examine the impact of coadministration of ethanol 1 g/kg on the safety and tolerability of EZG and the consequences of coadministration on pharmacokinetic (PK) and pharmacodynamic (PD) parameters in healthy volunteers.
  
  
  METHODS
  In a randomized, 4-way crossover, partially double-blind study, volunteers received 4 oral treatments (EZG 200 mg + ethanol placebo [light apple juice]; placebo + ethanol 1 g/kg; EZG 200 mg + ethanol 1 g/kg; or placebo + ethanol placebo) separated by 5 to 21 days.
  
  
  RESULTS
  PK and PD parameters were evaluated in 17 healthy volunteers (19 to 55 years) who were currently moderate alcohol drinkers. Ethanol coadministration increased EZG AUC(0-∞) and C(max) by 36% and 23%, respectively. EZG had no impact on ethanol PK. Ethanol alone impaired balance, blurred vision, and increased intoxication and dizziness. Objective tests (reaction times, response accuracy, attention, and manual tracking) were also impaired by ethanol. EZG treatment alone had no impact on PD measures other than a variable, transient increase in blurred vision (vision clear-crisp visual analog scale scores). Treatments were generally tolerated, with no serious adverse events or discontinuations owing to adverse events.
  
  
  CONCLUSIONS
  Ethanol increased EZG exposure, which did not seem to be clinically relevant. Except for an increase in blurred vision, impairment effects observed were related primarily to ethanol and were not exacerbated by the addition of EZG, which was generally tolerated with or without ethanol.
authors: Valeant Pharmaceuticals, Durham, North Carolina, USA. chris.crean@valeant.com
authors: Christopher S
authors: CS
authors: Crean
authors: Debra J
authors: DJ
authors: Tompson
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001288:Attention / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010655:Phenylenediamines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D014785:Vision, Ocular / Q000187:drug effects; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine; D000431:Ethanol