NEW YORK (Reuters Health) - Results of a study conducted in Japan suggest that cytochrome P450 (CYP3A4) activity, estimated using exogenous cortisol as a probe, can be utilized to tailor docetaxel therapy to individual patients.
Docetaxel is metabolized by CYP3A4 but the activity of this enzyme varies as much as 20-fold between individuals, which accounts for the large interpatient differences in the disposition of docetaxel, note Dr. Noboru Yamamoto and colleagues from the National Cancer Center Hospital in Tokyo.
In a previous study, the researchers established that docetaxel clearance correlates well with CYP3A4 clearance of cortisol, and they developed a formula based on urinary measurement of a metabolite of exogenous cortisol to predict docetaxel clearance.
The formula incorporates urinary 6-beta-hydroxycortisol excretion over 24 hours after a 300-mg IV dose of cortisol, alpha1-acid glycoprotein (AAG), aspartate aminotransferase (AST), and patient age.
In the current study, in the February 20 issue of the Journal of Clinical Oncology, the investigators randomized 59 patients with advanced non-small-cell lung cancer to traditional docetaxel dosing based on body surface area (BSA) or to CYP3A4-based docetaxel dosing.
Thirty patients in the BSA arm received 60 mg/m² of docetaxel. For the remaining 29 patients, individualized doses were calculated and ranged from 37.4 to 76.4 mg/m² with a mean dose of 58.1 mg/m².
Dr. Yamamoto’s group reports that CYP3A4-based docetaxel dosing significantly decreased interpatient variability in docetaxel area-under-the-curve (AUC) relative to BSA-based dosing.
“The standard deviation of AUC in the individualized arm was about 46.2% smaller than that in the BSA-based arm, a significant difference,” they note.
“Assuming that the variability of AUC could be decreased 46.2% by individualized dosing applying our method, overtreatment could be avoided in 14.5% of BSA-dosed patients by using individualized dosing and undertreatment could be avoided in another 14.5% of these patients,” the team contends.
They also report that the interpatient variability in percent decrease in absolute neutrophil count was slightly smaller in the individualized arm than in the BSA arm and fewer patients in the individualized dosing arm experienced grade 3-4 neutropenia (86% vs 93%).
The co-authors of an editorial note that “with refinement, pharmacogenetically based drug dosing holds great promise for optimizing doses of chemotherapy drugs or drug regimens to provide biologically active doses tailored to an individual’s ability to metabolize administered agents to maximize efficacy and minimize toxicity.” Source: J Clin Oncol 2005;23:1053-1055,1061-1069. [ Google search on this article ]
MeSH Headings: Biological Sciences : Biology : Carcinoma, Non-Small-Cell Lung : Cytochrome P-450 : Cytochromes : Enzymes, Coenzymes, and Enzyme Inhibitors : Genetics : Hydroxylases : Lung Neoplasms : Neoplasms : Neoplasms by Site : Pharmacogenetics : Respiratory Tract Neoplasms : Thoracic Neoplasms : Biological Sciences : Chemicals and Drugs : Diseases Copyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
