title: Effect of nalmefene 20 and 80 mg on the corrected QT interval and T-wave morphology: a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, single-centre study.
abstract: BACKGROUND
  Nalmefene is an orally administered competitive opioid receptor antagonist targeted at reducing alcohol consumption in alcohol-dependent patients. As part of the regulatory requirements for drug approval, the potential of novel compounds for causing unwanted proarrhythmia should be studied in a thoroughly designed clinical QT/corrected QT (QTc) study (International Conference on Harmonisation [ICH] E14 guideline).
  
  
  OBJECTIVE
  This study was designed to evaluate whether nalmefene 20 and 80 mg/day induced changes in cardiac repolarization biomarkers indicative of proarrhythmia (the QTc interval and T-wave morphology).
  
  
  METHODS
  This was a prospective, randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, single-centre study carried out in a clinical pharmacology unit. The study included 270 healthy male and female subjects (age 18-45 years). The subjects were randomized to a 7-day treatment period of placebo, nalmefene 20 mg/day or nalmefene 80 mg/day, or placebo for 6 days followed by a single dose of moxifloxacin 400 mg on day 7. Serial triplicate ECGs were obtained over a 24-hour period at protocol-defined time-points. The primary protocol-defined endpoint was the largest time-matched baseline- and placebo-adjusted mean difference in the individually heart rate-corrected QT interval (QTcNi) recorded at any of the 12 ECG time-points distributed over a 24-hour period on day 7 of treatment. Secondary endpoints included a similar analysis using the Fridericia- (QTcF) and Bazett-corrected (QTcB) intervals. An explorative analysis included quantitative assessment of T-wave morphology using the T-wave morphology composite score (MCS) to assess for differences between treatment groups and placebo on day 7 of treatment. The frequency of outliers in the QTc intervals, the pharmacokinetics of nalmefene and the tolerability of nalmefene were also assessed.
  
  
  RESULTS
  Nalmefene was rapidly absorbed with a time to reach maximum plasma concentration of 2.2 hours and a dose-proportionate relationship between dose administered and exposure. The largest baseline- and placebo-adjusted mean changes from baseline in the individualized QTcNi (primary endpoint) were 5.45 ms (90% CI 1.52, 9.37) and 5.57 ms (90% CI 1.62, 9.52) for nalmefene 20 and 80 mg/day, respectively, with study sensitivity confirmed by the expected largest increase in mean QTcNi of 10.15 ms (90% CI 5.67, 14.63) for moxifloxacin. Quantitative assessment using the T-wave MCS demonstrated the largest baseline- and placebo-adjusted increase in MCS to be non-significantly different from the intra-subject variability of triplicate recordings in the placebo group. No deaths or serious adverse events occurred in the study.
  
  
  CONCLUSIONS
  This thorough QT/QTc study was a negative study in accordance with the ICH E14 guideline, meaning that nalmefene has no clinically relevant effect on the QTc interval and T-wave morphology. The study predicts no concern over proarrhythmia or need for intensive QTc monitoring with the use of nalmefene in clinical practice.
authors.affiliation: H. Lundbeck A/S, Copenhagen, Denmark. jmat@lundbeck.com
authors.forename: Jørgen
authors.initials: J
authors.lastname: Matz
authors.forename: Claus
authors.initials: C
authors.lastname: Graff
authors.forename: Petri J
authors.initials: PJ
authors.lastname: Vainio
authors.forename: Antero
authors.initials: A
authors.lastname: Kallio
authors.forename: Astrid Maria
authors.initials: AM
authors.lastname: Højer
authors.forename: Johannes J
authors.initials: JJ
authors.lastname: Struijk
authors.forename: Jørgen K
authors.initials: JK
authors.lastname: Kanters
authors.forename: Mads P
authors.initials: MP
authors.lastname: Andersen
authors.forename: Egon
authors.initials: E
authors.lastname: Toft
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D001372:Aza Compounds / Q000009:adverse effects / Q000494:pharmacology; D054316:Biomarkers, Pharmacological; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D017408:Guidelines as Topic; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D000077266:Moxifloxacin; D009271:Naltrexone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010919:Placebos; D011446:Prospective Studies; D011804:Quinolines / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D054316:Biomarkers, Pharmacological; D024841:Fluoroquinolones; D009292:Narcotic Antagonists; D010919:Placebos; D011804:Quinolines; D009271:Naltrexone; C038981:nalmefene; D000077266:Moxifloxacin