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

Noboru Yamamoto, Tomohide Tamura, Haruyasu Murakami, Tatsu Shimoyama, Hiroshi Nokihara, Yutaka Ueda, Ikuo Sekine, Hideo Kunitoh, Yuichiro Ohe, Tetsuro Kodama, Mikiko Shimizu, Kazuto Nishio, Naoki Ishizuka, Nagahiro Saijo

Research output: Contribution to journalArticle

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Abstract

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-β-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 × 10-4 × total 6-β-OHF] - [4.02 × alpha-1 acid glycoprotein] - [0.172 × AST] - [0.125 × 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-β-OHF after cortisol administration can decrease PK variability of docetaxel.

Original languageEnglish
Pages (from-to)1061-1069
Number of pages9
JournalJournal of Clinical Oncology
Volume23
Issue number6
DOIs
Publication statusPublished - 2005 Feb 20
Externally publishedYes

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docetaxel
Body Surface Area
Cytochrome P-450 Enzyme System
Hydrocortisone
Pharmacokinetics
Cytochrome P-450 CYP3A
Neutrophils
Orosomucoid
Neutropenia
Non-Small Cell Lung Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Yamamoto, Noboru; Tamura, Tomohide; Murakami, Haruyasu; Shimoyama, Tatsu; Nokihara, Hiroshi; Ueda, Yutaka; Sekine, Ikuo; Kunitoh, Hideo; Ohe, Yuichiro; Kodama, Tetsuro; Shimizu, Mikiko; Nishio, Kazuto; Ishizuka, Naoki; Saijo, Nagahiro.

In: Journal of Clinical Oncology, Vol. 23, No. 6, 20.02.2005, p. 1061-1069.

Research output: Contribution to journalArticle

Yamamoto, N, Tamura, T, Murakami, H, Shimoyama, T, Nokihara, H, Ueda, Y, Sekine, I, Kunitoh, H, Ohe, Y, Kodama, T, Shimizu, M, Nishio, K, Ishizuka, N & Saijo, N 2005, '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', Journal of Clinical Oncology, vol. 23, no. 6, pp. 1061-1069. https://doi.org/10.1200/JCO.2005.11.036
Yamamoto, Noboru ; Tamura, Tomohide ; Murakami, Haruyasu ; Shimoyama, Tatsu ; Nokihara, Hiroshi ; Ueda, Yutaka ; Sekine, Ikuo ; Kunitoh, Hideo ; Ohe, Yuichiro ; Kodama, Tetsuro ; Shimizu, Mikiko ; Nishio, Kazuto ; Ishizuka, Naoki ; Saijo, Nagahiro. / 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. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 6. pp. 1061-1069.
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abstract = "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-β-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 × 10-4 × total 6-β-OHF] - [4.02 × alpha-1 acid glycoprotein] - [0.172 × AST] - [0.125 × 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-β-OHF after cortisol administration can decrease PK variability of docetaxel.",
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T1 - Randomized pharmacokinetic and pharmacodynamic study of docetaxel

T2 - Dosing based on body-surface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol

AU - Yamamoto, Noboru

AU - Tamura, Tomohide

AU - Murakami, Haruyasu

AU - Shimoyama, Tatsu

AU - Nokihara, Hiroshi

AU - Ueda, Yutaka

AU - Sekine, Ikuo

AU - Kunitoh, Hideo

AU - Ohe, Yuichiro

AU - Kodama, Tetsuro

AU - Shimizu, Mikiko

AU - Nishio, Kazuto

AU - Ishizuka, Naoki

AU - Saijo, Nagahiro

PY - 2005/2/20

Y1 - 2005/2/20

N2 - 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-β-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 × 10-4 × total 6-β-OHF] - [4.02 × alpha-1 acid glycoprotein] - [0.172 × AST] - [0.125 × 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-β-OHF after cortisol administration can decrease PK variability of docetaxel.

AB - 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-β-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 × 10-4 × total 6-β-OHF] - [4.02 × alpha-1 acid glycoprotein] - [0.172 × AST] - [0.125 × 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-β-OHF after cortisol administration can decrease PK variability of docetaxel.

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