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A Bayesian population physiologically based pharmacokinetic absorption modeling approach to support generic drug development: application to bupropion hydrochloride oral dosage forms

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Abstract

We propose a Bayesian population modeling and virtual bioequivalence assessment approach to establishing dissolution specifications for oral dosage forms. A generalizable semi-physiologically based pharmacokinetic absorption model with six gut segments and liver, connected to a two-compartment model of systemic disposition for bupropion hydrochloride oral dosage forms was developed. Prior information on model parameters for gut physiology, bupropion physicochemical properties, and drug product properties were obtained from the literature. The release of bupropion hydrochloride from immediate-, sustained- and extended-release oral dosage forms was described by a Weibull function. In vitro dissolution data were used to assign priors to the in vivo release properties of the three bupropion formulations. We applied global sensitivity analysis to identify the influential parameters for plasma bupropion concentrations and calibrated them. To quantify inter- and intra-individual variability, plasma concentration profiles in healthy volunteers that received the three dosage forms, each at two doses, were used. The calibrated model was in good agreement with both in vitro dissolution and in vivo exposure data. Markov Chain Monte Carlo samples from the joint posterior parameter distribution were used to simulate virtual crossover clinical trials for each formulation with distinct drug dissolution profiles. For each trial, an allowable range of dissolution parameters (“safe space”) in which bioequivalence can be anticipated was established. These findings can be used to assure consistent product performance throughout the drug product life-cycle and to support manufacturing changes. Our framework provides a comprehensive approach to support decision-making in drug product development.

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Acknowledgements

Funding for this work was made possible, in part, by the U.S. Environmental Protection Agency (STAR RD84003201), U.S Food and Drug Administration (1U01FD005838) and U.S. National Institute of Environmental Health Sciences (P42 ES027704). This article reflects the views of the author and should not be construed to represent FDA’s views or policies. Views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organizations imply endorsement by the United States Government.

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Author notes

  1. Nan-Hung Hsieh and Frédéric Y. Bois have contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA

    Nan-Hung Hsieh & Weihsueh A. Chiu

  2. Simcyp Division, Certara UK Limited, Sheffield, UK

    Frédéric Y. Bois

  3. Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Eleftheria Tsakalozou, Zhanglin Ni & Miyoung Yoon

  4. Office of Biostatistics, Division of Biometrics VIII, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Wanjie Sun & Martin Klein

  5. Chemical and Biological Engineering and School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA

    Brad Reisfeld

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  1. Nan-Hung Hsieh
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Contributions

N-HH, FYB, ET, and WAC conceived the overall research concept and design. N-HH performed most analyses, simulations, and preliminary manuscript writing. FYB developed the physiologically based pharmacokinetic absorption model and most computational experiment design. ET, ZN, MY, WS, and MK from the U.S. FDA reviewed the manuscript and provide critical comments during the whole research period. BR is the main funding acquisition and project administration.

Corresponding author

Correspondence to Weihsueh A. Chiu.

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Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Frédéric Y. Bois is currently employed by the CERTARA company but has no conflict of interest.

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Hsieh, NH., Bois, F.Y., Tsakalozou, E. et al. A Bayesian population physiologically based pharmacokinetic absorption modeling approach to support generic drug development: application to bupropion hydrochloride oral dosage forms. J Pharmacokinet Pharmacodyn 48, 893–908 (2021). https://doi.org/10.1007/s10928-021-09778-5

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