Assessment of cytochrome P450 3A4-mediated drug-drug interactions for ipatasertib using a fit-for-purpose physiologically based pharmacokinetic model.

ABSTRACT:

Purpose

Ipatasertib, a potent and highly selective small-molecule inhibitor of AKT, is currently under investigation for treatment of cancer. Ipatasertib is a substrate and a time-dependent inhibitor of CYP3A4. It exhibits non-linear pharmacokinetics at subclinical doses in the clinical dose escalation study. To assess the DDI risk of ipatasertib at the intended clinical dose of 400 mg with CYP3A4 inhibitors, inducers, and substrates, a fit-for-purpose physiologically based pharmacokinetic (PBPK) model of ipatasertib was developed.

Methods

The PBPK model was constructed in Simcyp using in silico, in vitro, and clinical data and was optimized and verified using clinical data.

Results

The PBPK model described non-linear pharmacokinetics of ipatasertib and captured the m

SUBMITTER: Jing J 

PROVIDER: S-EPMC9054915 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature