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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This work was supported by NIH intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Dr. Lorenzo Leggio), jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA); and by the National Center for Advancing Translational Sciences (NCATS) grant UH2/UH3-TR000963 (PIs: Drs Lorenzo Leggio and Fatemeh Akhlaghi). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The authors would like to thank the clinical and research staff involved in data collection and support at the NIAAA Division of Intramural Clinical and Biological Research, i.e., in the NIAAA/NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (in particular Christian Frable, Allison Daurio and Sara Deschaine), in the Section on Molecular Pathophysiology (in particular Andrew Pilling and Caroline Rauffenbart) and in the NIAAA clinical intramural program. The authors would also like to thank the research staff involved in samples and data analysis in the Clinical Pharmacokinetics Research Laboratory at the University of Rhode Island (in particular Anitha Sravankumar, Ben Barlock and Sravani Adusumalli). The authors would also like to thank the clinical and research staff involved in data collection and patient care at the NIH Clinical Center, i.e., in the Department of Nursing (in particular the nurses of the 1SE Inpatient Unit and of the 1-HALC 1SE Outpatient Clinic), in the Department of Nutrition (in particular LT Kelly Ratteree, MPH, RDN and CDR Merel Kozlosky, MS, RD) and in the Department of Pharmacy. The authors would also like to thank Ms. Karen Smith and Ms. Holly Thompson from the NIH Library for bibliographic assistance. Furthermore, the authors would like to express their gratitude to the participants who took part in this study. Finally, the authors would like to thank the Steering Committee of the UH2/UH3-TR000963 grant (PIs: Drs Lorenzo Leggio and Fatemeh Akhlaghi) whose members included members from the NIAAA Division of Medication Development (in particular Dr. Joanne Fertig), the Drug Development Partnership Programs of the National Center for Advancing Translational Sciences (NCATS) and Pfizer, which kindly provided the study drug under the NCATS grant UH2/UH3-TR000963. Pfizer did not have any role in the study design, execution or interpretation of the results, and this publication does not necessarily represent the official views of Pfizer.
Study neuroscientific basis, rationale, concept and design: LL; Provided funding: LL, MH, and FA; Statistical analysis: MRL, JDT, MLS, and FA; Acquisition and management of data: MRL, JDT, MG, AAD, ANL, EC, LAF, SB, MF, MH, FA, and LL; Clinical and Safety monitoring: MRL, and LL; Administrative, technical, or material support: MRL, JDT, MG, MLS, AAD, ANL, EC, LAF, SB, MF, MH, FA, and LL; Analysis and interpretation of data: MRL, JDT, MG, MLS, AAD, ANL, EC, LAF, SB, MF, MH, FA, and LL; Drafting the manuscript: MRL, and LL. All authors have critically reviewed the manuscript for important intellectual content and approved the final version of the manuscript.
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The authors declare that they have no conflict of interest.
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Lee, M.R., Tapocik, J.D., Ghareeb, M. et al. The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study. Mol Psychiatry 25, 461–475 (2020). https://doi.org/10.1038/s41380-018-0064-y
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