Abstract
Background and Objectives
The ghrelin receptor (GHS-R1a) is a potential target for alcohol use disorders. PF-5190457 is the first inverse agonist of GHS-R1a to progress to clinical development with potential to treat alcohol use disorder. We present a population pharmacokinetic model for PF-5190457 in non-heavy (alcohol consumption status = 0) and heavy alcohol drinkers (alcohol consumption status = 1), and identify relevant factors that can influence its pharmacokinetics.
Methods
Plasma concentration–time data from non-heavy (n = 35) and heavy drinkers (n = 12) were pooled for the population pharmacokinetic model development. The influence of various covariates including alcohol consumption status was evaluated. The accuracy, precision, and robustness of the model were also evaluated using bootstrapping and visual predictive checks.
Results
A two-compartment model best described the pharmacokinetics of PF-5190457. The apparent volume of distribution of 44.5 L, apparent clearance of 72.0 L/h, apparent peripheral volume of distribution of 271 L, apparent distributional clearance of 28.7 L/h, and first-order absorption rate constant of 0.27/h were accurate and precise. The apparent volume of distribution was 3.8-fold higher (169 L) in heavy drinkers, and correlated with a lower maximum plasma concentration in heavy drinkers compared with non-heavy drinkers at the same dose; and a corresponding reduced incidence of somnolence in heavy drinkers at doses > 50 mg.
Conclusions
This work provides an accurate, precise, and robust two-compartment model that describes the pharmacokinetics of PF-5190457 and suggests a possible link of PF-5190457 pharmacokinetics with somnolence.
Trial Registration
ClinicalTrials.gov identifier numbers NCT01247896 and NCT02039349
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Availability of Data and Material
A request to obtain phase I data should be made to Pfizer. Phase Ib data in subjects with alcohol use disorder will be available upon request.
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Acknowledgements
The authors thank the research staff of the Clinical Pharmacokinetics Research Laboratory at the University of Rhode Island. The authors also acknowledge the help of Drs. Ayman El-Kattan and Santos Carvajal-Gonzalez from Pfizer (Cambridge, MA, USA) for their help in providing the data of the phase Ia clinical study. The authors also thank the clinical and research staff involved in data collection and support at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, i.e., in the NIAAA/National Institute on Drug Abuse Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology and in the NIAAA clinical intramural program (especially Dr. Melanie Schwandt from the NIAAA Office of the Clinical Director). The authors additionally thank the clinical and research staff involved in data collection and patient care at the National Institutes of Health 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, and in the Department of Pharmacy. Furthermore, the authors are grateful to the participants who took part in this study. Finally, the authors thank the Steering Committee of the UH2/UH3-TR000963 grant (principal investigators: 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.
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Contributions
Modeling and simulation planning: EC, MRL, LL, and FA. Conduct of modeling and simulation: EC and FA. Drafting of manuscript: EC, MRL, LL, and FA. Revisions: EC, MRL, LL, and FA. Approval of submitted version: EC, MRL, LL, and FA.
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Funding
This work was funded by the National Center for Advancing Translational Sciences grant UH2/UH3-TR000963 (principal investigators: Drs. Lorenzo Leggio and Fatemeh Akhlaghi). This work was also supported by National Institutes of Health intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; principal investigator: Dr. Lorenzo Leggio), jointly funded by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism and the Intramural Research Program of the National Institute on Drug Abuse. 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.
Conflicts of Interest/Competing Interest
Enoch Cobbina, Mary R. Lee, Lorenzo Leggio, and Fatemeh Akhlaghi have no conflicts of interest that are directly relevant to the content of this article.
Ethics Approval
Two phase I clinical studies were conducted by Pfizer in healthy volunteers. Studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki, all International Conference on Harmonisation Good Clinical Practice Guidelines, and all local regulatory requirements (in particular, those affording greater protection to the safety of trial participants). Final study protocols and informed consent documents were reviewed and approved by the participating research centers and by an independent ethical committee or institutional review board. The principal investigator was required to inform the independent ethical committee or institutional review board of the study’s progress and any serious and/or unexpected adverse events. The phase Ib study in subjects with alcohol use disorder was approved by the National Institutes of Health Addictions Institutional Review Board and monitored by a data safety monitoring board.
Consent to Participate
Written, signed, and dated informed consent was obtained from participants prior to inclusion in the study. The phase Ia study in subjects with alcohol use disorder was conducted under a federal Certificate of Confidentiality. The use of PF-5190457 in this study was under the US Food and Drug Administration Investigational New Drug 119,365.
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Not applicable.
Code Availability
The NONMEM code for this study can be shared upon request.
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Cobbina, E., Lee, M.R., Leggio, L. et al. A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers. Clin Pharmacokinet 60, 471–484 (2021). https://doi.org/10.1007/s40262-020-00942-7
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DOI: https://doi.org/10.1007/s40262-020-00942-7