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Cancer Chemotherapy and Pharmacology

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Open Access 01-10-2020 | Drug Interaction | Original Article

Physiologically based pharmacokinetic modeling to assess metabolic drug–drug interaction risks and inform the drug label for fedratinib

Authors: Fan Wu, Gopal Krishna, Sekhar Surapaneni

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2020

Abstract

Purpose

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.

Methods

The physiologically based pharmacokinetic (PBPK) model of fedratinib was constructed in Simcyp^® (V17R1) by integrating available in vitro and in vivo information and was further parameterized and validated by using clinical PK data.

Results

The validated PBPK model was applied to predict DDIs between fedratinib and CYP modulators or substrates. The model simulations indicated that the fedratinib-as-victim DDI extent in terms of geometric mean area under curve (AUC) at steady state is about twofold or 1.2-fold when strong or moderate CYP3A4 inhibitors, respectively, are co-administered with repeated doses of fedratinib. In addition, the PBPK model successfully captured the perpetrator DDI effect of fedratinib on a sensitive CY3A4 substrate midazolam and predicted minor effects of fedratinib on CYP2C8/9 substrates.

Conclusions

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.

Available only for authorised users

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Title: Physiologically based pharmacokinetic modeling to assess metabolic drug–drug interaction risks and inform the drug label for fedratinib
Authors: Fan Wu
Gopal Krishna
Sekhar Surapaneni
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keywords: Drug Interaction
Ketoconazole
Repaglinide
Midazolam
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04131-y

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