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Integrating Forward and Reverse Translation in PBPK Modeling to Predict Food Effect on Oral Absorption of Weakly Basic Drugs

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Abstract

Introduction

Ketoconazole and posaconazole are two weakly basic broad-spectrum antifungals classified as Biopharmaceutics Classification System class II drugs, indicating that they are highly permeable, but exhibit poor solubility. As a result, oral bioavailability and clinical efficacy can be impacted by the formulation performance in the gastrointestinal system. In this work, we have leveraged in vitro biopharmaceutics and clinical data available in the literature to build physiologically based pharmacokinetic (PBPK) models for ketoconazole and posaconazole, to determine the suitability of forward in vitro-in vivo translation for characterization of in vivo drug precipitation, and to predict food effect.

Methods

A stepwise modeling approach was utilized to derive key parameters related to absorption, such as drug solubility, dissolution, and precipitation kinetics from in vitro data. These parameters were then integrated into PBPK models for the simulation of ketoconazole and posaconazole plasma concentrations in the fasted and fed states.

Results

Forward in vitro-in vivo translation of intestinal precipitation kinetics for both model drugs resulted in poor predictions of PK profiles. Therefore, a reverse translation approach was applied, based on limited fitting of precipitation-related parameters to clinical data. Subsequent simulations for ketoconazole and posaconazole demonstrated that fasted and fed state PK profiles for both drugs were adequately recapitulated.

Conclusion

The two examples presented in this paper show how middle-out modeling approaches can be used to predict the magnitude and direction of food effects provided the model is verified on fasted state PK data.

Graphical Abstract

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Data Availability

All data used in this research was obtained from public reports and referenced.

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Acknowledgements

The authors would like to thank Simulations Plus, Lancaster, CA for sponsoring this research and for providing academic licenses of DDDPlus™ and GastroPlus to the Center for Pharmacometrics and Systems Pharmacology at the University of Florida.

Funding

This study was sponsored by Simulations Plus, Lancaster, CA (No. AWD08034).

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Authors and Affiliations

  1. Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA

    Yesenia L. Franco, Lais Da Silva, Nitin Charbe, Hannah Kinvig, Soyoung Kim & Rodrigo Cristofoletti

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  1. Yesenia L. Franco
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  2. Lais Da Silva
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Correspondence to Rodrigo Cristofoletti.

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RC was an external member of the Simulations Plus scientific advisory board. All the other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper.

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Franco, Y.L., Da Silva, L., Charbe, N. et al. Integrating Forward and Reverse Translation in PBPK Modeling to Predict Food Effect on Oral Absorption of Weakly Basic Drugs. Pharm Res 40, 405–418 (2023). https://doi.org/10.1007/s11095-023-03478-0

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