Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel

Clin Pharmacol Ther. 2004 May;75(5):448-54. doi: 10.1016/j.clpt.2004.01.001.


Objective: In vitro studies indicate that the anticancer drug docetaxel is primarily eliminated by cytochrome P450 (CYP) 3A4-mediated metabolism. Coadministration of drugs that modulate the activity of CYP3A4 is, therefore, likely to have undesirable clinical consequences. We investigated the effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of docetaxel in patients with cancer.

Methods: Seven patients were treated in a randomized crossover design with docetaxel (100 mg/m(2)), followed 3 weeks later by docetaxel (10 mg/m(2)) given in combination with orally administered ketoconazole (200 mg once daily for 3 days), or the reverse sequence. Plasma concentration-time data were analyzed by noncompartmental analysis.

Results: Ketoconazole coadministration resulted in a 49% decrease in clearance of docetaxel (P =.018). The mean (+/-SD) clearance values were 35.0 +/- 11.8 L/h (95% confidence interval, 24.1-45.9 L/h) for docetaxel alone and 18.2 L/h (95% confidence interval, 9.22-27.1 L/h) in the presence of ketoconazole, respectively. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the area under the curve of ketoconazole (R(2) = 0.529, P =.064).

Conclusion: Inhibition of CYP3A4 by ketoconazole in vivo results in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dose reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacokinetics*
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Docetaxel
  • Drug Administration Schedule
  • Drug Interactions
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Ketoconazole / administration & dosage
  • Ketoconazole / pharmacology*
  • Male
  • Middle Aged
  • Taxoids / administration & dosage
  • Taxoids / pharmacokinetics*


  • Antifungal Agents
  • Antineoplastic Agents, Phytogenic
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Taxoids
  • Docetaxel
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ketoconazole