1. Integrating Dynamic in vitro Systems and Mechanistic Absorption Modeling: Case Study of Pralsetinib.
- Author
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Dolton MJ, Bowman C, Ma F, Cheeti S, Kuruvilla D, Kassir N, Chen Y, Liu J, and Chiang PC
- Subjects
- Humans, Administration, Oral, Solubility, Intestine, Small metabolism, Intestine, Small drug effects, Computer Simulation, Models, Biological, Intestinal Absorption drug effects
- Abstract
Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V., Weteringbrug, The Netherlands) is a dynamic in vitro model with close simulation of the successive physiological conditions of the human stomach and small intestine. Tiny-TIM runs with pralsetinib were performed at doses of 200 mg and 400 mg under fasting conditions. Mechanistic modeling of absorption was performed in Simcyp V21 (Certara, Manchester, UK). Pralsetinib fasted bioaccessibility in the Tiny-TIM system was 63% at 200 mg and 53% at 400 mg; a 16% reduction at 400 mg was observed under elevated gastric pH. Maximum pralsetinib solubility from the small intestinal compartment in Tiny-TIM directly informed the supersaturation/precipitation model parameters. The PBPK model predicted a similar fraction absorbed at 200 mg and 400 mg, consistent with the dose proportional increases in observed pralsetinib exposure. Integrating dynamic in vitro systems with mechanistic absorption modeling provides a promising approach for understanding and predicting human absorption with challenging low solubility compounds., Competing Interests: Declaration of conflict of interest All authors declare no competing interests for this work. CB, FM, SC, DK, NK, YC JL and P-CC are employees of Genentech Inc, a member of the Roche Group and may hold stock or options. MJD is an employee of Roche Products Pty Ltd, a member of the Roche Group and may hold stock or options., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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