Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects
-
Richat Abbas
,
Joseph Boni
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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©2015 by De Gruyter
Artikel in diesem Heft
- Frontmatter
- Editorial
- From DMDI “Drug Metabolism and Drug Interactions” to DMPT “Drug Metabolism and Personalized Therapy”
- Review
- Clinical drug-drug interactions: focus on venlafaxine
- Reviews in Population Pharmacogenomics
- Pharmacogenetics in Central American healthy volunteers: interethnic variability
- Genomic biomarkers related to drug response in Venezuelan populations
- Originial Articles
- No effect of CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) on lipid-lowering response to statins in Greek patients with primary hypercholesterolemia
- Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans
- Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects
- Minor contribution of biliary excretion in lithium elimination in rats
- Case Report
- Fatal hyperkalemia following succinylcholine administration in a child on oral propranolol
Artikel in diesem Heft
- Frontmatter
- Editorial
- From DMDI “Drug Metabolism and Drug Interactions” to DMPT “Drug Metabolism and Personalized Therapy”
- Review
- Clinical drug-drug interactions: focus on venlafaxine
- Reviews in Population Pharmacogenomics
- Pharmacogenetics in Central American healthy volunteers: interethnic variability
- Genomic biomarkers related to drug response in Venezuelan populations
- Originial Articles
- No effect of CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) on lipid-lowering response to statins in Greek patients with primary hypercholesterolemia
- Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans
- Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects
- Minor contribution of biliary excretion in lithium elimination in rats
- Case Report
- Fatal hyperkalemia following succinylcholine administration in a child on oral propranolol
