C. Ono,1 P. Hsyu,2 R. Abbas,3 C. Loi,2 S. Yamazaki2; 1Pfizer Japan Inc., Tokyo, Japan, 2Pfizer Inc., San Diego, CA, 3Pfizer Inc., Collegeville, PA

BACKGROUND: Bosutinib, an orally available dual Src/Abl tyrosine kinase inhibitor, has been approved globally for the treatment of adult patients with chronic myelogenous leukemia with resistance or intolerance to prior therapy. Since bosutinib is primarily metabolized by CYP3A4, clinical drug-drug interaction (DDI) studies of bosutinib with ketoconazole and rifampicin were conducted to assess its DDI potential. The objective of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bosutinib to assess potential effects of moderate CYP3A inhibitors on systemic exposures of bosutinib following oral administration.
METHODS: The PBPK model of bosutinib was developed based on the physicochemical properties and in vitro/in vivo pharmacokinetic data using Simcyp® (version 13.1). The model was then verified with the results from clinical DDI studies of bosutinib with and without concomitant repeated-dose administration of ketoconazole (400 mg once daily) or rifampin (600 mg once daily). Subsequently, this PBPK model was applied to predict bosutinib DDIs with moderate CYP3A inhibitors such as fluconazole and erythromycin.
RESULTS: Bosutinib PBPK model developed with its Phase I study results was reasonably verified with the clinical DDI studies showing 6.5-fold increase in bosutinib oral exposures (estimated as AUC) by ketoconazole and 13-fold decrease in bosutinib exposures by rifampin. The simulation results predicted that oral exposures of bosutinib could be increased significantly with co-administration of moderate CYP3A inhibitors.
CONCLUSION: Bosutinib PBPK model developed and verified in the present study can be utilized to predict oral exposures of bosutinib in other clinical studies