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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  CYP 3A by evofosfamide administered weekly is unlikely to occur in humans. Moreover, static and  PBPK  modeling showed no clinically relevant inhibition via  CYP 2B6,  CYP 2D6, and  CYP 3A4. In conclusion,  PBPK  models were used to supplement  in vitro  information of a cytotoxic compound. This approach may set a precedent for future studies of cytotoxic drugs, potentially reducing the need for clinical  DDI  studies and providing more confidence in the clinical use of approved cytotoxic compounds for which  DDI  information is sparse.

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