Opioid Receptor Modulation of Hedonic Taste Preference and Food Intake: A Single‐Dose Safety, Pharmacokinetic, and Pharmacodynamic Investigation With GSK1521498, a Novel μ‐Opioid Receptor Inverse Agonist

Abstract

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

Erratum: Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects

“…26,55,56 GSK1521498 was generally well tolerated compared with placebo, with no deleterious effects detected on anxiety, mood or other aspects of hedonic function or on liver or other blood safety parameters. Akin to previous studies, 31,32 transient impairments on subjective ratings of alertness, contentedness and calmness, were seen with GSK1521498 on the first day of active treatment, largely driven by relative increases in the placebo group. Therefore, the only central effects of GSK1521498 identified were mild and not clinically significant.…”

“…The designated primary efficacy endpoints were body weight, fat mass and BES scores. 36,37 Aspects of hedonic responses and eating behaviour were examined during the inpatient visits on Days À 1, 14 and 28 using three paradigms: (i) hedonic taste preference; 31,41 (ii) ad libitum snacking; 31,41 and (iii) ad libitum buffet dining. At approximately 1245 hours, subjects were asked to quantify on a nine-point scale (ranging from 'dislike extremely' to 'like extremely'), hedonic responses to dairy products of varying fat and sugar content.…”

“…11,30 GSK1521498 is a novel opioid antagonist being investigated as a candidate treatment for behavioural and substance addictions. [31][32][33] It is centrally active and has 14-20-fold greater selectivity for mu versus kappa and delta opioid receptors. 31 In rodents, GSK1521498 suppressed the intake of standard and palatable chow and caused weight loss in diet-induced obese rats.…”

“…35 In a single dose (25 mg) phase 1 study in healthy overweight men, GSK1521498 reduced the pleasurable response to high-fat and high-sugar food samples and reduced calorie intake in an ad libitum eating experiment. 31 The current study evaluated the effects of 28 days of GSK1521498 treatment on a range of parameters in binge-eating obese individuals. We hypothesised that, compared with placebo, treatment with GSK1521498 would cause significant reductions in hedonic responses to food and calorific intake, decrease bingeeating severity and consequently result in weight loss. )…”

The role of fMRI in drug development

“…The complementary value of fMRI when combined with RO-PET, providing central PD in addition to target engagement data, was illustrated in a combined RO-PET and fMRI study of novel (GSK1521498) and comparator (naltrexone) M-opioid antagonists [134], compounds that had been studied as potential therapeutics in disorders of compulsive consumption [135–137]. The fMRI paradigm was designed to test the hypothesis that these compounds attenuate the functional brain response to a palatable gustatory stimulus.…”