Drug–Drug Interaction Potential of Marketed Oncology Drugs: In Vitro Assessment of Time-Dependent Cytochrome P450 Inhibition, Reactive Metabolite Formation and Drug–Drug Interaction Prediction
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To evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug–drug interaction (DDI) risk using static mechanistic models.
Human liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of KI and kinact. Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI.
Negative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The kinact/KI ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent–drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected.
13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors.
KEY WORDSdrug-drug interaction kinase inhibitors prediction reactive metabolites time-dependent CYP inhibition
area under the curve
average plasma concentration
maximum plasma concentration
human liver microsomes
tandem mass spectrometry
new molecular entity
physiologically based pharmacokinetic modeling
ACKNOWLEDGMENTS & DISCLOSURES
We thank Dr Cornelis ECA Hop for encouragement to investigate these oncology drugs and members of Genentech DMPK for valuable discussions.
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