Development and application of a physiologically based pharmacokinetic model for entrectinib in rats and scale-up to humans: Route-dependent gut wall metabolism - 16/01/22
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Abstract |
Entrectinib (Rozlytrek®) is an oral antineoplastic agent approved by the U.S. Food and Drug Administration in 2019 for the treatment of c-ros oncogene 1 (ROS1)-positive non-small cell lung cancer and neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumors. Although there have been a few studies on the pharmacokinetics of entrectinib, the relative contributions of several kinetic factors determining the oral bioavailability and systemic exposure of entrectinib are still worthy of investigation. Experimental data on the intestinal absorption and disposition of entrectinib in rats were acquired from studies on in vitro protein binding/tissue S9 metabolism, in situ intestinal perfusion, and in vivo dose-escalation/hepatic extraction. Using these datasets, an in-house whole-body physiologically based pharmacokinetic (PBPK) model incorporating the QGut model concepts and segregated blood flow in the gut was constructed and optimized with respect to drug-specific parameters. The established rat PBPK model was further extrapolated to humans through relevant physiological scale-up and parameter optimization processes. The optimized rat and human PBPK models adequately captured the impact of route-dependent gut metabolism on the systemic exposure to entrectinib and closely mirrored various preclinical and clinical observations. Our proposed PBPK model could be useful in optimizing dosage regimens and predicting drug interaction potential in various clinical conditions, after partial modification and validation.
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Highlights |
• | Focus on kinetic factors determining oral BA and systemic exposure of entrectinib. |
• | PBPK model incorporated the QGut model with segregated blood flow in the gut. |
• | Rat PBPK model was constructed using in vitro permeation and metabolism data. |
• | Human PBPK model was established by interspecies scale-up and parameter optimization. |
• | PBPK model adequately captured the route-dependent gut extraction of entrectinib. |
Keywords : Entrectinib, PBPK model, QGut model, Segregated gut blood flow, Rat, Human
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Vol 146
Article 112520- février 2022 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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