A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and caucasian cancer patients: CALGB 9871

Lionel D. Lewis, Antonius A. Miller, Gary L. Rosner, Jonathan E. Dowell, Manuel Valdivieso, Mary V. Relling, Merrill J. Egorin, Robert R. Bies, Donna R. Hollis, Ellis G. Levine, Gregory A. Otterson, Frederick Millard, Mark J. Ratain

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3302-3311
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number11
DOIs
StatePublished - Jun 1 2007

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docetaxel
Cytochrome P-450 CYP3A
African Americans
Pharmacokinetics
Neoplasms
Neutrophils
Confidence Intervals
Pharmacogenetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and caucasian cancer patients : CALGB 9871. / Lewis, Lionel D.; Miller, Antonius A.; Rosner, Gary L.; Dowell, Jonathan E.; Valdivieso, Manuel; Relling, Mary V.; Egorin, Merrill J.; Bies, Robert R.; Hollis, Donna R.; Levine, Ellis G.; Otterson, Gregory A.; Millard, Frederick; Ratain, Mark J.

In: Clinical Cancer Research, Vol. 13, No. 11, 01.06.2007, p. 3302-3311.

Research output: Contribution to journalArticle

Lewis, LD, Miller, AA, Rosner, GL, Dowell, JE, Valdivieso, M, Relling, MV, Egorin, MJ, Bies, RR, Hollis, DR, Levine, EG, Otterson, GA, Millard, F & Ratain, MJ 2007, 'A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and caucasian cancer patients: CALGB 9871', Clinical Cancer Research, vol. 13, no. 11, pp. 3302-3311. https://doi.org/10.1158/1078-0432.CCR-06-2345
Lewis, Lionel D. ; Miller, Antonius A. ; Rosner, Gary L. ; Dowell, Jonathan E. ; Valdivieso, Manuel ; Relling, Mary V. ; Egorin, Merrill J. ; Bies, Robert R. ; Hollis, Donna R. ; Levine, Ellis G. ; Otterson, Gregory A. ; Millard, Frederick ; Ratain, Mark J. / A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and caucasian cancer patients : CALGB 9871. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 11. pp. 3302-3311.
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abstract = "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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T1 - A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and caucasian cancer patients

T2 - CALGB 9871

AU - Lewis, Lionel D.

AU - Miller, Antonius A.

AU - Rosner, Gary L.

AU - Dowell, Jonathan E.

AU - Valdivieso, Manuel

AU - Relling, Mary V.

AU - Egorin, Merrill J.

AU - Bies, Robert R.

AU - Hollis, Donna R.

AU - Levine, Ellis G.

AU - Otterson, Gregory A.

AU - Millard, Frederick

AU - Ratain, Mark J.

PY - 2007/6/1

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N2 - 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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