Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Oct 2020
Physiologically based pharmacokinetic modeling to assess metabolic drug-drug interaction risks and inform the drug label for fedratinib.
Fedratinib (INREBIC®), a Janus kinase 2 inhibitor, is approved in the United States to treat patients with myelofibrosis. Fedratinib is not only a substrate of cytochrome P450 (CYP) enzymes, but also exhibits complex auto-inhibition, time-dependent inhibition, or mixed inhibition/induction of CYP enzymes including CYP3A. Therefore, a mechanistic modeling approach was used to characterize pharmacokinetic (PK) properties and assess drug-drug interaction (DDI) potentials for fedratinib under clinical scenarios. ⋯ The PBPK-DDI model of fedratinib facilitated drug development by identifying DDI potential, optimizing clinical study designs, supporting waivers for clinical studies, and informing drug label claims. Fedratinib dose should be reduced to 200 mg QD when a strong CYP3A4 inhibitor is co-administered and then re-escalated to 400 mg in a stepwise manner as tolerated after the strong CYP3A4 inhibitor is discontinued.