Open AccessA Novel PBPK Modeling Approach to Assess Cytochrome P450 Mediated Drug‐Drug Interaction Potential of the Cytotoxic Prodrug Evofosfamide
Author(s) -
Lüpfert Christian,
Dyroff Martin,
Richter Oliver,
Gallemann Dieter,
El Bawab Samer,
Dolgos Hugues,
Jung Don,
Hecht Stefan,
Johne Andreas
Publication year - 2018
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12360
Subject(s) - physiologically based pharmacokinetic modelling , prodrug , pharmacology , drug , cyp2b6 , pharmacokinetics , cyp3a4 , chemistry , in vitro , cytotoxic t cell , cytochrome p450 , medicine , biochemistry , metabolism
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.