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

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.<

SUBMITTER: Wu F 

PROVIDER: S-EPMC7515950 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature