• Open Access

The effects of alcohol on the pharmacokinetics and pharmacodynamics of the selective mu-opioid receptor antagonist GSK1521498 in healthy subjects

Authors

  • Hisham Ziauddeen MRCPsych,

    Corresponding author
    1. Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
    2. Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
    3. Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK
    • Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
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  • Pradeep J. Nathan PhD, FCP,

    1. Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
    2. Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
    3. School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia
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  • Chris Dodds PhD,

    1. Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
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  • Kay Maltby BSc(Hons),

    1. Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
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  • Sam R. Miller BA, MSc,

    1. Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
    2. Projects Clinical Platforms and Sciences, GlaxoSmithKline, Stevenage, UK
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  • Dawn Waterworth PhD,

    1. Projects Clinical Platforms and Sciences, GlaxoSmithKline, King of Prussia, PA, USA
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  • Kijoung Song PhD,

    1. Projects Clinical Platforms and Sciences, GlaxoSmithKline, King of Prussia, PA, USA
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  • Liling Warren PhD,

    1. Projects Clinical Platforms and Sciences, GlaxoSmithKline, Research Triangle Park, NC, USA
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  • Louise Hosking BSc(Hons),

    1. Projects Clinical Platforms and Sciences, GlaxoSmithKline, Stevenage, UK
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  • Mauro Zucchetto MSc,

    1. GlaxoSmithKline Research and Development Ltd, Medicines Research Centre, Stevenage, UK
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  • Mark Bush PhD,

    1. Kinetigen, Research Triangle Park, NC, USA
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  • Lakshmi Vasist Johnson PharmD,

    1. Kinetigen, Research Triangle Park, NC, USA
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  • Bhopinder Sarai BSc(Hons),

    1. Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
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  • Karin Mogg PhD,

    1. Department of Psychology, University of Southampton, Southampton, UK
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  • Brendan P. Bradley PhD,

    1. Department of Psychology, University of Southampton, Southampton, UK
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  • Duncan B. Richards DM, MRCP,

    1. Academic Discovery Performance Unit, GlaxoSmithKline, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
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  • Paul C. Fletcher PhD, MRCPsych,

    1. Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
    2. Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
    3. Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK
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  • Edward T. Bullmore MB, PhD, MRCPsych

    1. Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
    2. Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
    3. Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK
    4. Academic Discovery Performance Unit, GlaxoSmithKline, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK
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Corresponding Author:

Hisham Ziauddeen, GSK Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge Biomedical Campus, Cambridge CB2 2GG, UK

Email: hz238@cam.ac.uk

Abstract

The mu-opioid system has a key role in hedonic and motivational processes critical to substance addiction. However, existing mu-opioid antagonists have had limited success as anti-addiction treatments. GSK1521498 is a selective and potent mu-opioid antagonist being developed for the treatment of overeating and substance addictions. In this study, 28 healthy participants were administered single doses of GSK1521498 20 mg, ethanol 0.5 g/kg body weight, or both in combination, in a double blind placebo controlled four-way crossover design. The primary objective was to determine the risk of significant adverse pharmacodynamic and pharmacokinetic (PK) interactions. The effects of GSK1521498 on hedonic and consummatory responses to alcohol and the attentional processing of alcohol-related stimuli, and their modulation by the OPRM1 A118G polymorphism were also explored. GSK1521498 20 mg was well tolerated alone and in combination with ethanol. There were mild transient effects of GSK1521498 on alertness and mood that were greater when it was combined with ethanol. These effects were not of clinical significance. There were no effects of GSK1521498 on reaction time, hedonic or consummatory responses. These findings provide encouraging safety and PK data to support continued development of GSK1521498 for the treatment of alcohol addiction.

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