title: Cardiac repolarization with Gabapentin enacarbil in a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.
abstract: BACKGROUND
  Gabapentin enacarbil (GEn) is a prodrug of gabapentin and is approved in the United States in adults for the management of postherpetic neuralgia and in the United States and Japan for the treatment of moderate-to-severe primary restless legs syndrome.
  
  
  OBJECTIVE
  This study examined the lack of effect of GEn on cardiac repolarization in accordance with International Conference on Harmonisation E14 guidance.
  
  
  METHODS
  This was a randomized, double-blind, double-dummy, placebo- and active- controlled, crossover study in healthy adults (age range, 18-50 years). Study participants received the following in randomized order with a minimum 7-day washout period between treatments: placebo at 0 hours and GEn 1200 mg at 2 hours (GEn 1200 mg group), placebo at 0 hours and GEn 6000 mg at 2 hours (GEn 6000 mg group), placebo at 0 and 2 hours (placebo group), moxifloxacin 400 mg (active control group) at 0 hours, and placebo at 2 hours (moxifloxacin group). Dose offsetting permitted moxifloxacin to be administered in the fasted state and GEn to be administered in the fed state. Assessments included continuous ECG monitoring, pharmacokinetic parameters, and safety and tolerability profiles. The primary end point was the change from baseline in the Fridericia corrected QT interval, at each time point, for the GEn 6000 mg and placebo groups.
  
  
  RESULTS
  Of 52 adults enrolled (mean [SD] age, 30.8 [8.55] years; 50% women), 44 adults (85%) completed the study. Forty-nine adults received GEn 1200 mg, 47 received GEn 6000 mg, 48 received placebo, and 47 received moxifloxacin. The highest estimated (upper limit of the 95% CI) model-adjusted difference in mean change from baseline in the Fridericia corrected QT interval between GEn and placebo was 3.55 (5.66) msec for 1200 mg and 1.20 (3.32) msec for 6000 mg. Assay sensitivity was confirmed with moxifloxacin 400 mg. The geometric mean (%CV) Cmax (between-subject coefficient of variation) was 7.49 (21.2) μg/mL for GEn 1200 mg, 32.46 (23.9) μg/mL for GEn 6000 mg, and 2.08 (24.5) μg/mL for moxifloxacin 400 mg. The most frequently reported adverse events with GEn 6000 mg were dizziness (30%), feeling drunk (26%), nausea (15%), headache (13%), and vomiting (13%).
  
  
  CONCLUSIONS
  Single doses of GEn, up to 6000 mg, had no effect on cardiac repolarization in this thorough-QT study and are unlikely to cause clinically relevant QT prolongation in clinical use. Assay sensitivity was confirmed with moxifloxacin as an active control. ClinicalTrials.gov identifier: NCT01516372.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom. Electronic address: Maria.Davy@gsk.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Davy
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Upward
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Thangam
authors.initials: T
authors.lastname: Arumugham
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Colleen
authors.initials: C
authors.lastname: Twomey
authors.affiliation: GlaxoSmithKline, Stockley Park, United Kingdom.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Brendt
authors.initials: B
authors.lastname: Stier
mesh_terms: D000293:Adolescent; D000328:Adult; D001372:Aza Compounds / Q000008:administration & dosage / Q000009:adverse effects; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D001372:Aza Compounds; D002219:Carbamates; D024841:Fluoroquinolones; D011804:Quinolines; D005680:gamma-Aminobutyric Acid; D000077266:Moxifloxacin
keywords: QTc prolongation; cardiac repolarization; gabapentin enacarbil; pharmacokinetic profile