Physiologically based pharmacokinetic modeling of ponatinib to describe drug-drug interactions in patients with cancer.

ABSTRACT

PURPOSE: This study aimed to investigate the drug-drug interactions of ponatinib with strong, moderate, or weak CYP3A4 inhibitors/inducers by developing physiologically based pharmacokinetic (PBPK) models. METHODS: Simcyp® Ver 20.1 (Certara Inc., Sheffield, UK) was used to construct a PBPK model for ponatinib and to predict its interaction with strong, moderate, or weak CYP3A4 inhibitors/inducers. The constructed model was validated by comparing predicted values with actual observed values. Inhibitors or inducers that increased or decreased the area under the plasma concentration curve of ponatinib by more than two-fold when used in combination were considered significant. RESULTS: The PBPK model of ponatinib accurately represented its oral pharmacokinetics. It also reasonably predicted its pharmacokinetics when combined with ketoconazole and rifampicin. No weak to strong CYP3A4 inhibitor combinations significantly increased the AUC of ponatinib. However, the strong CYP3A4 inducers rifampicin (oral, 600 mg QD) and phenytoin (oral, 100 mg TID) decreased AUC by 60-70% and 50%, respectively. CONCLUSIONS: The PBPK model predicted a significant drug interaction when ponatinib was combined with a strong CYP3A4 inducer. Conversely, the combination with weak-to-strong CYP3A4 inhibitors did not suggest a drug interaction with ponatinib.