A Novel PBPK Modeling Approach to Assess Cytochrome P450 Mediated Drug-Drug Interaction Potential of the Cytotoxic Prodrug Evofosfamide.

ABSTRACT: Evofosfamide is a cytotoxic small-molecule prodrug preferentially activated under hypoxic conditions. The cytotoxicity of evofosfamide impacted the generation of in vitro drug-drug interaction (DDI) data, especially in vitro induction results. Therefore, a novel physiologically based pharmacokinetic (PBPK) approach was used, which involved available in vitro and clinical data of evofosfamide and combined it with induction data from the prototypical cytochrome P450 (CYP)3A inducer rifampicin. The area under the concentration-time curve (AUC) ratios of midazolam were above 0.80, indicating that induction of CYP3A by evofosfamide administered weekly is unlikely to occur in humans. Moreover, static and PBPK modeling showed no clinically relevant inhibition via CYP2B6, CYP2D6, and CYP3A4. In co

SUBMITTER: Lupfert C 

PROVIDER: S-EPMC6310869 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature