Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy subjects

J Clin Pharmacol. 2011 Dec;51(12):1721-7. doi: 10.1177/0091270010387427. Epub 2010 Dec 8.


Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of chronic myelogenous leukemia. The effect of coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib was evaluated in an open-label, randomized, 2-period, crossover study. Healthy subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with multiple once-daily doses of oral ketoconazole 400 mg. PK sampling occurred through 96 hours. The least square geometric mean treatment ratios (90% confidence interval [CI]) of C(max(bosutinib+ketoconazole))/C(max(bosutinib alone)), AUC(T(bosutinib+ketoconazole))/AUC(T(bosutinib alone)), and AUC((bosutinib+ketoconazole))/AUC((bosutinib alone)) were assessed. Compared with bosutinib administered alone, coadministration with ketoconazole increased bosutinib C(max) 5.2-fold, AUC(T) 7.6-fold, and AUC 8.6-fold. Ketoconazole coadministration decreased the mean apparent clearance of bosutinib approximately 9-fold and increased the mean (SD) terminal half-life from 46.2 (16.4) hours to 69.0 (29.1) hours. The incidence of adverse events (AEs) was comparable between the 2 treatments. The most common AEs were headache, nausea, and increased blood creatinine. No safety-related discontinuations or serious AEs occurred. These PK results indicate that bosutinib is susceptible to interaction with potent CYP3A4 inhibitors.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aniline Compounds / administration & dosage
  • Aniline Compounds / adverse effects
  • Aniline Compounds / pharmacokinetics*
  • Antifungal Agents / pharmacology
  • Area Under Curve
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors*
  • Drug Interactions
  • Humans
  • Ketoconazole / pharmacology*
  • Male
  • Middle Aged
  • Nitriles / administration & dosage
  • Nitriles / adverse effects
  • Nitriles / pharmacokinetics*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Quinolines / administration & dosage
  • Quinolines / adverse effects
  • Quinolines / pharmacokinetics*
  • Young Adult


  • Aniline Compounds
  • Antifungal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Nitriles
  • Protein Kinase Inhibitors
  • Quinolines
  • bosutinib
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Protein-Tyrosine Kinases
  • Ketoconazole