Cited by 130Regulation of Appetite and ObesityAlcohol Consumption and Health EffectsSubstance Abuse Treatment and Outcomes

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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

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Lee, Mary R., Tapocik, Jenica D., Ghareeb, Mwlod, Schwandt, Melanie L., Dias, Alexandra A., Le, April N., Cobbina, Enoch, Farinelli, Lisa A., Bouhlal, Sofia, Farokhnia, Mehdi, Heilig, Markus, Akhlaghi, Fatemeh, Leggio, Lorenzo·2020·Molecular Psychiatry

DOI 10.1038/s41380-018-0064-yPMC PMC6215751

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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.

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Authors: Lee, M. R., Tapocik, J. D., Ghareeb, M., Schwandt, M. L., Dias, A. A., Le, A. N., Cobbina, E., Farinelli, L. A., Bouhlal, S., Farokhnia, M., Heilig, M., Akhlaghi, F., & Leggio, L.
Affiliations: National Institutes of Health (US)
University of Rhode Island (US)
Linköping University (SE)
Corresponding author: Leggio, Lorenzo
ORCID: Lee, Mary R.
Schwandt, Melanie L.
Cobbina, Enoch
Farinelli, Lisa A.
Farokhnia, Mehdi
Heilig, Markus
Akhlaghi, Fatemeh
Leggio, Lorenzo
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2018-05-04
Volume: 25
Issue: 2
Pages: 461-475
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-018-0064-y
PMC: PMC6215751
OpenAlex: W2799409941
Cited by: 129
References: 69
Citations by year: 2026: 8 · 2025: 13 · 2024: 22 · 2023: 12 · 2022: 19 · 2021: 16 · 2020: 15 · 2019: 14 · 2018: 10
FWCI: 7.76
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Journal of Media Literacy Education (submittedVersion, cc-by)
Funders: National Institutes of Health (UH2TR000963, UH3TR000963)
National Institute on Alcohol Abuse and Alcoholism (ZIAAA000218)
National Center for Advancing Translational Sciences
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords: alcoholism, alcohol craving, alcohol cue reactivity, pharmacokinetics, pharmacodynamics, drug safety and tolerability, heavy drinkers, insulin-like growth factor I, locomotor activity
MeSH terms: Adult, Alcohol Drinking, Ethanol, Alcoholic Intoxication, Alcoholism, Animals, Azetidines, Female, Humans, Male, Middle Aged, Research Design, Spiro Compounds, Single-Blind Method, Rats, Wistar, Rats, Ghrelin, Receptors, Ghrelin

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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

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