Effect of Nalmefene 20 and 80 mg on the Corrected QT Interval and T-Wave Morphology
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Clin Drug Investig 2011; 31 (11): 799-811 1173-2563/11/0011-0799/$49.95/0
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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 Jørgen Matz,1 Claus Graff,2 Petri J. Vainio,3 Antero Kallio,3 Astrid Maria Højer,1 Johannes J. Struijk,2 Jørgen K. Kanters,4,5,6 Mads P. Andersen7 and Egon Toft7 1 H. Lundbeck A/S, Copenhagen, Denmark 2 Medical Informatics Group (MI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark 3 Biotie Therapies Corp., Turku, Finland 4 Department of Cardiology P, Gentofte University Hospital, Gentofte, Denmark 5 Danish National Research Foundation, Centre for Cardiac Arrhythmia (DARC), Laboratory of Experimental Cardiology, University of Copenhagen, Copenhagen, Denmark 6 Department of Cardiology S, Aalborg Hospital, Aarhus University Hospitals, Aalborg, Denmark 7 Center for Sensory Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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 protocoldefined 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
Matz et al.
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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
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