Originally published as JCO Early Release 10.1200/JCO.2005.11.036 on January 18 2005

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Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol

From the Division of Internal Medicine, National Cancer Center Hospital; Pharmacology Division and Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan

Address reprint requests to Tomohide Tamura, MD, Division of Internal Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; e-mail: ttamura{at}ncc.go.jp

PURPOSE: Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-ß-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) –based dosing.

PATIENTS AND METHODS: Fifty-nine patients with advanced non–small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m² of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 x 10^–4 x total 6-ß-OHF] – [4.02 x alpha-1 acid glycoprotein] – [0.172 x AST] – [0.125 x age]) and the target AUC of 2.66 mg/L · h.

RESULTS: In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m² (mean, 58.1 mg/m²). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L · h) and 0.40 mg/L · h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L · h) and 0.22 mg/L · h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm.

CONCLUSION: The individualized dosing method based on the total amount of urinary 6-ß-OHF after cortisol administration can decrease PK variability of docetaxel.

Supported in part by a Grant-in-Aid for Cancer Research (9–25) from the Ministry of Health, Labor, and Welfare, Tokyo, Japan.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18–21, 2002, Orlando, FL.

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

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• Role of Cytochrome P450 Phenotyping in Cancer Treatment
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