Background: Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor and a CYP3A4 enzyme substrate. This study assessed the safety, tolerability, and pharmacokinetics of bosutinib when coadministered with the CYP3A4 inducer rifampin in 24 healthy men.
Methods: Subjects received single oral doses of bosutinib 500 mg (Days 1 and 14) and once-daily oral doses of rifampin 600 mg (Days 8-17); serial blood samples were analyzed.
Results: Bosutinib exposures were reduced following concomitant administration of rifampin vs. bosutinib alone, measured by peak plasma concentration (C(max); 112 vs. 16.0 ng/mL; 86% reduction), total area under the concentration-time curve (AUC; 2740 vs. 207 ng·h/mL; 92% reduction), and AUC to the last measurable concentration at time T (2440 vs. 158 ng·h/mL; 94% reduction). Median time to C(max) and mean half-life were shorter for bosutinib plus rifampin vs. single-agent bosutinib. Oral clearance increased approximately 13-fold; the volume of distribution increased from 9560 to 72,900 L. Treatment-emergent adverse events appeared less frequently with bosutinib plus rifampin (59%) vs. single-agent bosutinib (79%); diarrhea was reported in 11 (46%) vs. 4 (18%) subjects, respectively.
Conclusions: Concomitant use of potent or moderate CYP3A inducers with bosutinib should be avoided because of the effects of drug-drug interaction observed between bosutinib and rifampin.
Trial registration: ClinicalTrials.gov NCT00725426.