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Clinical Trial
. 2010 Oct 20;28(30):4562-7.
doi: 10.1200/JCO.2010.30.7025. Epub 2010 Sep 20.

Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer

Ryan M Franke  1 , Michael A Carducci, Michelle A Rudek, Sharyn D Baker, Alex Sparreboom
Affiliations
Clinical Trial

Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer

Ryan M Franke et al. J Clin Oncol. .

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.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Effect of castration on (A) docetaxel clearance, (B) the area under the curve (AUC) of docetaxel normalized to 75 mg/m2, and (C) hepatic CYP3A4 activity as determined by the erythromycin breath test (ERMBT) in noncastrated (open squares, n = 10) and castrated (closed squares, n = 20 for docetaxel studies and n = 6 for ERMBT) patients with prostate cancer. Each square represents an observation in a single patient, and horizontal lines and error bars represent mean and SE, respectively.
Fig 2.
Fig 2.
Effect of castration on the concentration-time profile of docetaxel (10 mg/kg, iv) in (A) liver and (B) plasma of noncastrated (gold squares) and castrated (blue squares) Sprague-Dawley rats and on the hepatic expression of solute carriers and adenosine triphosphate binding cassette transporters as measured by (C) microarray or (D) real-time quantitative polymerase chain reaction (n = three to four animals per time point) in noncastrated (gold bars) and castrated (blue bars) Sprague-Dawley rats. (E) Transport of docetaxel in water-injected control (gold bar) Xenopus laevis oocytes or those expressing the rat Oat2 transporter (blue bar, n = 22 observations per group). All data are shown as mean (symbol or bar) and SE (error bar). *P < .05; †P < .01; ‡P < .001.
Fig 3.
Fig 3.
Effect of (A) docetaxel concentration, (B) incubation time, and (D) erythromycin on the transport of docetaxel by the human OAT2 transporter in HEK293 cells and (C) effect of OAT2 on docetaxel-induced growth inhibition. All data are shown as mean (symbol or bar) and SE (error bar) of 5 to 15 observations per group. VC, vector control. *P < .01; †P < .001.
Fig A1.
Fig A1.
Intracellular accumulation of erythromycin and docetaxel in HEK293 cells or Xenopus laevis oocytes overexpressing a variety of solute carriers. Transporters that have significant accumulation of drug, as compared with controls, are denoted by (a). There is substrate overlap in both docetaxel and erythromycin transport by Oatp1a1, Oatp1a4, OATP1B3, and Oatp1b2. However, only docetaxel is a substrate for OAT2, and only erythromycin is a substrate for OATP1A2 (denoted by b). Bars represent mean (% of control) and SE (error bar).
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