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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

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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 pharma-cokinetics 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 80mg/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.

Conclusion: 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.

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Acknowledgements

This study was co-sponsored by Biotie Therapies Corp., Turku, Finland and H. Lundbeck A/S, Copenhagen, Denmark. Jørgen Matz and Astrid Maria Højer are employees of Lundbeck A/S. C Graff, J.J. Struijk, M.P. Andersen and E. Toft are employees of Aalborg University, Aalborg, Denmark, which has filed patents on the ECG methodology used to determine T-wave morphology in this study and has a licence agreement for the methodology with GE Healthcare, Milwaukee, WI, USA. J.K. Kanters has filed patents on the ECG methodology used to determine T-wave morphology in this study and has a licence agreement for the methodology with GE Healthcare. P.J. Vainio and A. Kallio are employees of Biotie Therapies Corp.

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Authors and Affiliations

  1. H. Lundbeck A/S, Ottiliavej 9, 2500, Valby-Copenhagen, Denmark

    Jørgen Matz & Astrid Maria Højer

  2. Medical Informatics Group (MI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

    Claus Graff & Johannes J. Struijk

  3. Biotie Therapies Corp., Turku, Finland

    Petri J. Vainio & Antero Kallio

  4. Department of Cardiology P, Gentofte University Hospital, Gentofte, Denmark

    Jørgen K. Kanters

  5. Danish National Research Foundation, Centre for Cardiac Arrhythmia (DARC), Laboratory of Experimental Cardiology, University of Copenhagen, Copenhagen, Denmark

    Jørgen K. Kanters

  6. Department of Cardiology S, Aalborg Hospital, Aarhus University Hospitals, Aalborg, Denmark

    Jørgen K. Kanters

  7. Center for Sensory Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

    Mads P. Andersen & Egon Toft

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  1. Jørgen Matz
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Correspondence to Jørgen Matz.

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Matz, J., Graff, C., Vainio, P.J. et al. Effect of Nalmefene 20 and 80 mg on the Corrected QT Interval and T-Wave Morphology. Clin. Drug Investig. 31, 799–811 (2011). https://doi.org/10.1007/BF03256919

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