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Mechanistic Modeling of In Vitro Biopharmaceutic Data for a Weak Acid Drug: A Pathway Towards Deriving Fundamental Parameters for Physiologically Based Biopharmaceutic Modeling

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Abstract

Mechanistic modeling of in vitro experiments using metabolic enzyme systems enables the extrapolation of metabolic clearance for in vitro-in vivo predictions. This is particularly important for successful clearance predictions using physiologically based pharmacokinetic (PBPK) modeling. The concept of mechanistic modeling can also be extended to biopharmaceutics, where in vitro data is used to predict the in vivo pharmacokinetic profile of the drug. This approach further allows for the identification of parameters that are critical for oral drug absorption in vivo. However, the routine use of this analysis approach has been hindered by the lack of an integrated analysis workflow. The objective of this tutorial is to (1) review processes and parameters contributing to oral drug absorption in increasing levels of complexity, (2) outline a general physiologically based biopharmaceutic modeling workflow for weak acids, and (3) illustrate the outlined concepts via an ibuprofen (i.e., a weak, poorly soluble acid) case example in order to provide practical guidance on how to integrate biopharmaceutic and physiological data to better understand oral drug absorption. In the future, we plan to explore the usefulness of this tutorial/roadmap to inform the development of PBPK models for BCS 2 weak bases, by expanding the stepwise modeling approach to accommodate more intricate scenarios, including the presence of diprotic basic compounds and acidifying agents within the formulation.

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Funding

This research was supported by F. Hoffmann-La Roche Ltd. under the Roche Access to Distinguished Scientist (ROADS) and Technology, Innovation, and Science (TIS) programs in collaboration with the University of Florida.

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Authors and Affiliations

  1. Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics Lake Nona (Orlando), College of Pharmacy, University of Florida, 6550 Sanger Road, Office 467, Orlando, Florida, 32827, USA

    Venkata Krishna Kowthavarapu, Nitin Bharat Charbe, Churni Gupta, Tatiana Iakovleva, Stephan Schmidt & Rodrigo Cristofoletti

  2. Pharmaceutical Research & Development, Formulation & Process Development, F. Hoffmann—La Roche Ltd., 4070, Basel, Switzerland

    Cordula Stillhart

  3. Pharmaceutical Research & Early Development, Roche Innovation Center Basel, F. Hoffmann—La Roche Ltd., 4070, Basel, Switzerland

    Neil John Parrott

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  1. Venkata Krishna Kowthavarapu
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  2. Nitin Bharat Charbe
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  3. Churni Gupta
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  4. Tatiana Iakovleva
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  7. Stephan Schmidt
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  8. Rodrigo Cristofoletti
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Methodology, investigation, writing, review: Venkata Krishna Kowthavarapu; writing, review: Nitin Bharat Charbe; scientific editing, review: Churni Gupta and Tatiana Iakovleva; scientific editing, review, supervision: Cordula Stillhart, Neil John Parrott, and Stephan Schmidt; conceptualization, review, resources, supervision: Rodrigo Cristofoletti. All authors approved the submitted version.

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Correspondence to Rodrigo Cristofoletti.

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Kowthavarapu, V.K., Charbe, N.B., Gupta, C. et al. Mechanistic Modeling of In Vitro Biopharmaceutic Data for a Weak Acid Drug: A Pathway Towards Deriving Fundamental Parameters for Physiologically Based Biopharmaceutic Modeling. AAPS J 26, 44 (2024). https://doi.org/10.1208/s12248-024-00912-y

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