Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers

Abstract

Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. CLINICALTRIALS.GOV: NCT02039349. This article is part of the special issue on 'Neuropeptides'.

Keywords: Alcohol; Alcohol use disorder; GHS-R1a; Ghrelin; Heavy drinking; Hormones; Neuroendocrinology; PF-5190457.

Conflict of interest statement

Conflicts of interest

The authors declare that they have no conflict of interest.

Published by Elsevier Ltd.

Figures

Fig. 1.

Blood concentration [Mean ( ± SD)] of thyroid stimulating hormone (TSH) at 90 min before (timepoints 1,3,5) drug dosing on Day 1,2,3. Drug doses: Placebo, PF-5190457, 50 mg and 100 mg.

Fig. 2.

Blood concentration [Mean ( ± SD)] of insulin at 90 min before (timepoints 1,3,5) and 75 min after (timepoints 2,4,6) drug dosing on Day 1,2,3. Drug doses: Placebo, PF-5190457, 50 mg and 100 mg.

Fig. 3.

Blood concentration [Mean ( ± SD)] of amylin at 90 min before (timepoints 1,3,5) and 75 min after (timepoints 2,4,6) drug dosing on Day 1,2,3. Drug doses: Placebo, PF-5190457, 50 mg and 100 mg.

Fig. 4.

Heatmap representation of the difference in the hormone-concentration-time curve (AUC) encompassing Days 1,2,3 for the PF-5190457 100 mg minus the placebo conditions for each of the 12 subjects who completed the study (N101-N114). The heatmap analysis was limited to the hormones for which six timepoints were available during the dosing phase: amylin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), insulin, leptin, pancreatic polypeptide (PP), and peptide YY.

Fig. 5.

Blood concentrations [Mean ( ± SD)] of A) Insulin, B) Amylin, C) Gastrointestinal Peptide (GIP), and D) Leptin during the alcohol challenge, which was performed on Day 3. Alcohol was administered at +30, lunch at +210, and dinner at +570. Timepoints +1350 and + 1440 were not included in the analysis and their inclusion in the figures is only for illustrative purposes.