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Measuring the Impact of Gastrointestinal Variables on the Systemic Outcome of Two Suspensions of Posaconazole by a PBPK Model

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Abstract

For the last two decades, the application of physiologically based pharmacokinetic (PBPK) models has grown exponentially in the field of oral absorption and in a regulatory context. Although these models are widely used, their predictive power should be validated and optimized in order to rely on these models and to know exactly what is going on “under the hood”. In this study, an automated sensitivity analysis (ASA) was performed for 11 gastrointestinal (GI) variables that are integrated into the PBPK software program Simcyp®. The model of interest was a previously validated workspace that was able to predict the intraluminal and systemic behavior of two different suspensions of posaconazole in the Simcyp® Simulator. The sensitivity of the following GI parameters was evaluated in this model: gastric and duodenal pH, gastric and duodenal bicarbonate concentrations (reflecting buffer capacity), duodenal bile salts concentration, gastric emptying, the interdigestive migrating motor complex (IMMC), small intestinal transit time (SITT), gastric and jejunal volumes, and permeability. The most sensitive parameters were gastric/duodenal pH and gastric emptying, for both suspensions. The outcome of the sensitivity analyses highlights the important GI variables that must be integrated into an in vivo predictive dissolution test to help and create a rational and scientific framework/design for product development of novel and generic drug products.

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Disclaimer

This report represents the scientific views of the authors and not necessarily that of the FDA. Part of this work was presented at the Simcyp Virtual Webinar 2017—part II.

Funding

This work was supported by grant No. HHSF223201510157C and grant No. HHSF223201310144C by the US Food and Drug Administration (FDA). This work has received support from the internal funds of KU Leuven (PDM/17/164).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, Michigan, 48109-1065, USA

    Bart Hens, Arjang Talattof, Marival Bermejo, Yasuhiro Tsume & Gordon L. Amidon

  2. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000, Leuven, Belgium

    Bart Hens

  3. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal

    Paulo Paixão

  4. Department Engineering Pharmacy Section, Miguel Hernandez University, San Juan de Alicante, 03550, Alicante, Spain

    Marival Bermejo

  5. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

    Raimar Löbenberg

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  1. Bart Hens
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Hens, B., Talattof, A., Paixão, P. et al. Measuring the Impact of Gastrointestinal Variables on the Systemic Outcome of Two Suspensions of Posaconazole by a PBPK Model. AAPS J 20, 57 (2018). https://doi.org/10.1208/s12248-018-0217-6

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