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The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.

ABSTRACT: Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0?mg b.i.d., 50?mg b.i.d., 100?mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100?mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.

SUBMITTER: Lee MR

PROVIDER: S-EPMC6215751 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.

Lee Mary R MR Tapocik Jenica D JD Ghareeb Mwlod M Schwandt Melanie L ML Dias Alexandra A AA Le April N AN Cobbina Enoch E Farinelli Lisa A LA Bouhlal Sofia S Farokhnia Mehdi M Heilig Markus M Akhlaghi Fatemeh F Leggio Lorenzo L

Molecular psychiatry 20180504 2

Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a ...[more]

PMID: 29728704

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Project description:The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the "crosstalk" between ghrelin and inflammation by examining the effects of exogenous ghrelin administration and ghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms - an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) - each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F3,36 = 3.345, p = 0.030) and IL-10 (F3,53.2 = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.

Dataset Information

The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.

Publications

The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.

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