Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects

Cancer Chemother Pharmacol. 2004 Oct;54(4):290-4. doi: 10.1007/s00280-004-0832-z. Epub 2004 May 8.


The study under discussion was a drug-drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design. The treatment sequence was randomly allocated. Subtherapeutic imatinib doses and a short exposure were tested in order not to overexpose the healthy volunteers. There was a minimum 7-day washout period between the two sequences. Blood samples for determination of plasma concentrations were taken up to 96 h after dosing. Imatinib and CGP74588 (main metabolite of imatinib) concentrations were measured using LC/MS/MS method and pharmacokinetic parameters were estimated by a non-compartmental analysis. Following ketoconazole coadministration, the mean imatinib C(max), AUC((0-24)) and AUC((0- infinity )) increased significantly by 26% ( P<0.005), 40% ( P<0.0005) and 40% ( P <0.0005), respectively. There was a statistically significant decrease in apparent clearance (CL/f) of imatinib with a mean reduction of 28.6% ( P<0.0005). The mean C(max) and AUC((0-24)) of the metabolite CGP74588 decreased significantly by 22.6% ( P<0.005) and 13% ( P<0.05) after ketoconazole treatment, although the AUC((0- infinity )) of CGP74588 only decreased by 5% ( P=0.28). Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacokinetics*
  • Benzamides
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Drug Interactions
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Humans
  • Imatinib Mesylate
  • Ketoconazole / adverse effects
  • Ketoconazole / pharmacokinetics*
  • Male
  • Middle Aged
  • Piperazines / adverse effects
  • Piperazines / pharmacokinetics*
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacokinetics*


  • Antineoplastic Agents
  • Benzamides
  • CGP 74588
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Ketoconazole