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. The primary clearance pathway of bosutinib is CYP3A4-mediated metabolism; therefore, clinical drug-disease interactions were evaluated in patients with renal and hepatic impairments after a single oral administration of bosutinib. The objective of this study was to apply a physiologically-based pharmacokinetic (PBPK) model for bosutinib to predict the increases in bosutinib oral exposures in the disease populations following repeated-dose administration.
METHODS: The PBPK model of bosutinib was reasonably developed with Phase I study results using Simcyp® (version 13.1). Subsequently, the PBPK model was applied to predict the increases in single-dose oral exposures of bosutinib in patients with renal impairments (creatinine clearances of <30 and 30 to 60 mL/min) and hepatic impairments (Child-Pugh Classes A, B and C) following single- and repeated-dose oral administration.
RESULTS: The PBPK model of bosutinib reasonably predicted the increase in single-dose oral exposures in renal impairment patients showing the observed increase in AUC by ~1.5-fold. In contrast, the PBPK model tended to over-predict the increase in single-dose oral exposures in hepatic impairment patients showing the observed increase in AUC by ~2-fold.
CONCLUSION: Bosutinib PBPK model verified in the present study can be useful to predict oral exposures of bosutinib in renal impairment patients; however, further refinements of the PBPK model will be required to predict oral exposures in hepatic impairment patients.