Abstract
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 (Cmax; 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 Cmax 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.
Acknowledgments
The authors thank all of the subjects who participated in this study and the principal investigator, Patricia A. Chandler, MD, of Charles River Clinical Services Northwest Inc., Tacoma, WA. Medical writing assistance was provided by Kimberly Brooks, PhD, of SciFluent and was supported by Pfizer.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study (Study 3160A4-1106; ClinicalTrials.gov #NCT00725426) was sponsored by Wyeth Research, which was acquired by Pfizer Inc. in October 2009.
Employment or leadership: Richat Abbas is an employee of Pfizer Inc. At the time this study was conducted, Joseph Boni and Daryl Sonnichsen were employed by Wyeth Research and held stock in the corporation.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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