title: 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.
abstract: OBJECTIVE
  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-beta-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.
  
  
  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/m(2) 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-beta-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/m(2) (mean, 58.1 mg/m(2)). 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.
  
  
  CONCLUSIONS
  The individualized dosing method based on the total amount of urinary 6-beta-OHF after cortisol administration can decrease PK variability of docetaxel.
authors.affiliation: Division of Internal Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Tatsu
authors.initials: T
authors.lastname: Shimoyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.forename: Hideo
authors.initials: H
authors.lastname: Kunitoh
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kodama
authors.forename: Mikiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishizuka
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D019540:Area Under Curve; D001830:Body Surface Area; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone