1. Advancements in physiologically based pharmacokinetic modeling for fedratinib: updating dose guidance in the presence of a dual inhibitor of CYP3A4 and CYP2C19.
- Author
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Chang M, Chen Y, Ogasawara K, Schmidt BJ, and Gaohua L
- Subjects
- Humans, Pyrrolidines pharmacokinetics, Pyrrolidines administration & dosage, Cytochrome P-450 CYP3A metabolism, Sulfonamides pharmacokinetics, Sulfonamides administration & dosage, Neoplasms drug therapy, Dose-Response Relationship, Drug, Male, Female, Adult, Computer Simulation, Middle Aged, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents administration & dosage, Benzenesulfonamides, Drug Interactions, Cytochrome P-450 CYP3A Inhibitors administration & dosage, Cytochrome P-450 CYP3A Inhibitors pharmacokinetics, Models, Biological, Cytochrome P-450 CYP2C19 Inhibitors administration & dosage, Cytochrome P-450 CYP2C19 Inhibitors pharmacokinetics, Cytochrome P-450 CYP2C19 Inhibitors pharmacology, Cytochrome P-450 CYP2C19 metabolism
- Abstract
Purpose: A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug-drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance., Methods: The original minimal PBPK model was developed using Simcyp
® Simulator v17. The model was updated by substituting a single distribution rate (Qsac ) with 2 separate rates (CLin /CLout ) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole)., Results: Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state., Conclusions: The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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