Using molecularly dissolved drug concentrations in PBBMs improves the prediction of oral absorption from supersaturating formulations.

Autor: Holzem FL; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark; Pharmaceutical R&D, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland., Petrig Schaffland J; Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland., Brandl M; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark., Bauer-Brandl A; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark., Stillhart C; Pharmaceutical R&D, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2024 Mar 01; Vol. 194, pp. 106703. Date of Electronic Publication: 2024 Jan 14.
DOI: 10.1016/j.ejps.2024.106703
Abstrakt: Predicting the absorption of drugs from enabling formulations is still challenging due to the limited capabilities of standard physiologically based biopharmaceutics models (PBBMs) to capture complex absorption processes. Amongst others, it is often assumed that both, molecularly and apparently dissolved drug in the gastrointestinal lumen are prone to absorption. A recently introduced method for measuring concentrations of molecularly dissolved drug in a dynamic in vitro dissolution setup using microdialysis has opened new opportunities to test this hypothesis and refine mechanistic PBBM approaches. In the present study, we compared results of PBBMs that used either molecularly or apparently dissolved concentrations in the simulated gastrointestinal lumen as input parameters. The in vitro dissolution data from three supersaturating formulations of Posaconazole (PCZ) were used as model input. The modeling outcome was verified using PCZ concentration vs. time profiles measured in human intestinal aspirates and in the blood plasma. When using apparently dissolved drug concentrations (i.e., the sum of colloid-associated and molecularly dissolved drug) the simulated systemic plasma exposures were overpredicted, most pronouncedly with the ASD-based tablet. However, if the concentrations of molecularly dissolved drug were used as input values, the PBBM resulted in accurate prediction of systemic exposures for all three PCZ formulations. The present study impressively demonstrated the value of considering molecularly dissolved drug concentrations as input value for PBBMs of supersaturating drug formulations.
Competing Interests: Declarations of competition interest The authors report no conflicts of interest.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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