Premium
Effect of Cytochrome P450 3A4 Inhibition on the Pharmacokinetics of Docetaxel
Author(s) -
Engels Frederike K.,
Tije Albert J.,
Baker Sharyn D.,
Lee Carlton K. K.,
Loos Walter J.,
Vulto Arnold G.,
Verweij Jaap,
Sparreboom Alex
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.01.001
Subject(s) - ketoconazole , docetaxel , pharmacokinetics , cyp3a4 , pharmacology , medicine , drug interaction , crossover study , confidence interval , chemistry , chemotherapy , cytochrome p450 , metabolism , placebo , antifungal , alternative medicine , dermatology , pathology
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. Clinical Pharmacology & Therapeutics (2004) 75 , 448–454; doi: 10.1016/j.clpt.2004.01.001