The effects of alcohol on the pharmacokinetics and pharmacodynamics of the selective mu-opioid receptor antagonist GSK1521498 in healthy subjects.
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.
Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge, UK; Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK; Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK.
Hisham
H
Ziauddeen
Pradeep J
PJ
Nathan
Chris
C
Dodds
Kay
K
Maltby
Sam R
SR
Miller
Dawn
D
Waterworth
Kijoung
K
Song
Liling
L
Warren
Louise
L
Hosking
Mauro
M
Zucchetto
Mark
M
Bush
Lakshmi Vasist
LV
Johnson
Bhopinder
B
Sarai
Karin
K
Mogg
Brendan P
BP
Bradley
Duncan B
DB
Richards
Paul C
PC
Fletcher
Edward T
ET
Bullmore
D000328:Adult; D000339:Affect / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000235:genetics; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
D007189:Indans; C568078:N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D014230:Triazoles; D000431:Ethanol
OPRM1; addiction; alcohol; mu-opioid receptor; pharmacodynamics; pharmacogenetics; pharmacokinetics; safety