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

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.

Keywords: OPRM1; addiction; alcohol; mu-opioid receptor; pharmacodynamics; pharmacogenetics; pharmacokinetics; safety.

Figure 1

The chemical structure of GSK1521498. GSK1521498 (N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine phosphate (1:1)), GlaxoSmithKline, Research Triangle Park, NC.

Figure 2

Study design schematic. The upper panel illustrates the Part 1 pilot assessment for optimization of dose administration and sampling for pharmacokinetic assessments. The bottom panel illustrates the double-blind crossover Part 2 study.

Figure 3

Summary of VAS and POMS-B treatment effects. Significant effects are seen in GSK1521498 treatment periods at the 4-hour time point and in the GSK1521498 and ethanol periods at 7 hours on the VAS alertness and contentedness and POMS-B total mood disturbance. No effects are seen on VAS calmness. Ethanol was administered after the 4-hour time point, so there is no PD effect of ethanol at this time point (*P < .05).

Figure 4

Summary of Power of Attention (PoA) scores. Increases in reaction time were seen on Digit Vigilance, Simple Reaction Time, and Power of Attention score in treatment periods with ethanol at the 5-hour time point only. There were no effects or additional effects of GSK1521498 at any time point (*P < .05).