Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer

Abstract

Purpose: To assess whether the low incidence of severe neutropenia in castrated men with prostate cancer treated with docetaxel is the result of changes in systemic clearance. Patients and Methods: A total of 10 noncastrated and 20 castrated men with prostate cancer were studied to achieve 80% power (α = .05) to detect at least a 25% change in the clearance of docetaxel. The erythromycin breath test was evaluated to determine hepatic activity of cytochrome P450 3A4 (CYP3A4), the main docetaxel-metabolizing enzyme. Additional studies were performed in rats and transfected cells overexpressing human or rodent transporters. Results: Docetaxel clearance was increased by approximately 100% in castrated men and was associated with a two-fold reduction in area under the curve (P = .0001), although hepatic activity of CYP3A4 was unchanged (P = .26). In rats, castration was associated with higher uptake of docetaxel in the liver and a concurrent increase in the expression of rOat2 (Slc22a7), an organic anion transporter that regulates, in part, the transfer of docetaxel from the circulation into hepatocytes. Conclusion: It is recommended that castration- and/or hormone-related changes in the clearance of oncology drugs should be considered as a possible risk factor for treatment failure. © 2010 by American Society of Clinical Oncology.