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Mol Pharm. 2017 Dec 4;14(12):4321-4333. doi: 10.1021/acs.molpharmaceut.7b00396. Epub 2017 Sep 5.

In Silico Modeling Approach for the Evaluation of Gastrointestinal Dissolution, Supersaturation, and Precipitation of Posaconazole.

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College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109-1065, United States of America.
Drug Delivery & Disposition, KU Leuven , Leuven 3000, Belgium.
Simcyp Limited (a Certara Company) , Sheffield S2 4SU, United Kingdom.
Biopharmaceutics, Pharmaceutical Sciences & Clinical Supply, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States of America.
Sandoz, Inc., West Princeton, New Jersey 08540, United States of America.
Analytical Sciences, Pharmaceutical Sciences & Clinical Supply, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States of America.


The aim of this study was to evaluate gastrointestinal (GI) dissolution, supersaturation, and precipitation of posaconazole, formulated as an acidified (pH 1.6) and neutral (pH 7.1) suspension. A physiologically based pharmacokinetic (PBPK) modeling and simulation tool was applied to simulate GI and systemic concentration-time profiles of posaconazole, which were directly compared with intraluminal and systemic data measured in humans. The Advanced Dissolution Absorption and Metabolism (ADAM) model of the Simcyp Simulator correctly simulated incomplete gastric dissolution and saturated duodenal concentrations of posaconazole in the duodenal fluids following administration of the neutral suspension. In contrast, gastric dissolution was approximately 2-fold higher after administration of the acidified suspension, which resulted in supersaturated concentrations of posaconazole upon transfer to the upper small intestine. The precipitation kinetics of posaconazole were described by two precipitation rate constants, extracted by semimechanistic modeling of a two-stage medium change in vitro dissolution test. The 2-fold difference in exposure in the duodenal compartment for the two formulations corresponded with a 2-fold difference in systemic exposure. This study demonstrated for the first time predictive in silico simulations of GI dissolution, supersaturation, and precipitation for a weakly basic compound in part informed by modeling of in vitro dissolution experiments and validated via clinical measurements in both GI fluids and plasma. Sensitivity analysis with the PBPK model indicated that the critical supersaturation ratio (CSR) and second precipitation rate constant (sPRC) are important parameters of the model. Due to the limitations of the two-stage medium change experiment the CSR was extracted directly from the clinical data. However, in vitro experiments with the BioGIT transfer system performed after completion of the in silico modeling provided an almost identical CSR to the clinical study value; this had no significant impact on the PBPK model predictions.


PBPK; absorption; biopharmaceutics classification system; clinical trial simulation; formulation; gastrointestinal; intestinal absorption; mechanistic physiological model; oral absorption; oral drug delivery; precipitation; supersaturation

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