Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib

Clin Cancer Res. 2007 Dec 15;13(24):7394-400. doi: 10.1158/1078-0432.CCR-07-0346.


Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib.

Experimental design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4). The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes.

Results: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) microg.h/mL and 41.2 (32.1-53.1) microg.h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 micromol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro.

Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Benzamides
  • Biological Availability
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / drug effects
  • Drug Interactions
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Gastrointestinal Stromal Tumors / drug therapy
  • Humans
  • Imatinib Mesylate
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Piperazines / pharmacokinetics*
  • Piperazines / therapeutic use
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / therapeutic use
  • Ritonavir / pharmacokinetics*
  • Ritonavir / therapeutic use


  • Antineoplastic Agents
  • Benzamides
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ritonavir