Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects

• Published in: Drug metabolism and drug interactions Vol. 30; no. 1; pp. 57 - 63
• Main Authors: Abbas, Richat, Boni, Joseph, Sonnichsen, Daryl
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 01.03.2015; Walter de Gruyter GmbH
• Subjects: Administration, Oral; Adult; Aniline Compounds - administration & dosage; Aniline Compounds - adverse effects; Aniline Compounds - pharmacokinetics; Area Under Curve; bosutinib; CYP3A induction; CYP3A4; Cytochrome P-450 CYP3A Inducers - administration & dosage; Cytochrome P-450 CYP3A Inducers - adverse effects; Cytochrome P-450 CYP3A Inducers - pharmacology; Drug Administration Schedule; Drug Combinations; drug information; Drug Interactions; drug-drug interactions; Female; Healthy Volunteers; Humans; Male; Middle Aged; Nitriles - administration & dosage; Nitriles - adverse effects; Nitriles - pharmacokinetics; oncology; pharmacokinetics; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - pharmacokinetics; rifampin; Rifampin - administration & dosage; Rifampin - adverse effects; Rifampin - pharmacology; tyrosine kinase inhibitor; Young Adult
• ISSN: 2363-8907; 0792-5077; 2363-8915; 2191-0162
• DOI: 10.1515/dmdi-2014-0026

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. 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. Bosutinib exposures were reduced following concomitant administration of rifampin vs. bosutinib alone, measured by peak plasma concentration (C ; 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 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. 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.