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A Comparison of the Pharmacokinetics and Pharmacodynamics of Docetaxel between African-American and Caucasian Cancer Patients: CALGB 9871

Authors' Affiliations: ¹ Sections of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, Dartmouth Medical School and The Norris Cotton Cancer Center, Lebanon, New Hampshire; ² Comprehensive Cancer Center of Wake Forest University, Winston Salem, North Carolina; ³ Cancer and Leukemia Group B Statistical Center, Duke University, Durham, North Carolina; ⁴ Department of Hematology and Oncology, University of Texas Southwestern and Dallas Veterans Affairs Medical Center, Dallas, Texas; ⁵ Department of Pharmaceutical Sciences, St. Jude Research Hospital, Memphis, Tennessee; ⁶ Departments of Medicine, ⁷ Pharmaceutical Sciences and Psychiatry, Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, ⁸ Roswell Park Cancer Institute, Buffalo, New York; ⁹ The Ohio State University Medical Center, Columbus, Ohio; ¹⁰ University of California at San Diego, San Diego, California; and ¹¹ Department of Medicine, University of Chicago, Chicago, Illinois

Requests for reprints: Lionel D. Lewis, Sections of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, Dartmouth Medical School and Dartmouth Hitchcock Medical Center, Lebanon, NH 03756. Phone: 603-650-8685; Fax: 603-650-6841; E-mail: Lionel.D.Lewis{at}Dartmouth.edu.

Purpose: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients.

Experimental Design: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m² as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done.

Results: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied.

Conclusions: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.

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