Population pharmacokinetics of weekly docetaxel in patients with advanced cancer.
OBJECTIVE
Previous pharmacokinetic studies of the 3-weekly regimen (100 mg m(-2) every 3 weeks) of docetaxel have shown that docetaxel clearance is affected by liver function, body surface area, age, serum alpha1-acid glycoprotein and cytochrome P450 3A4 (CYP3A4) activity. However, the pharmacokinetics of a weekly docetaxel (40 mg m(-2) week(-1)) schedule are not well characterized. The aims of this study were (a) to investigate the pharmacokinetics of docetaxel (40 mg m(-2) week(-1)) using sparse concentration-time data collected from patients with advanced cancer and (b) to utilize a population pharmacokinetic approach to identify patient covariates that significantly influence the clearance of docetaxel when administered according to this regimen.


METHODS
A two-compartment pharmacokinetic model was used to describe the docetaxel concentration-time data from 54 patients with advanced cancer. The mean population and individual posterior Bayesian estimates of docetaxel clearance were estimated using P-PHARM. The relationships between docetaxel clearance and 21 covariates were investigated. This included estimates of CYP3A4 function in each patient using the erythromycin breath test (1/tmax). Significant covariates were included into the final population pharmacokinetic model. Pharmacokinetic models were validated using a data splitting approach with a dataset consisting of 16 patients.


RESULTS
Significant relationships were found between docetaxel clearance and 1/tmax (erythromycin breath test parameter) and several of the liver function enzymes and CL was best described by the equation; CL = 21.51 + 217 (1/tmax) - 0.13 (ALT). This final population pharmacokinetic model provided both precise and unbiased predictions of docetaxel concentrations in a validation group of patients and an estimate of the population mean (95% confidence interval) clearance of docetaxel was 30.13 l h(-1) (12.54, 46.04 l h(-1)) with an intersubject variability 30%.


CONCLUSIONS
A population pharmacokinetic model has been developed and validated for weekly docetaxel (40 mg m(-2)) in patients with advanced cancer. These results indicate that CYP3A4 activity and hepatic function have an impact on the pharmacokinetics of docetaxel when administered weekly.
Slaviero
Kellie A
KA
Department of Pharmacology, University of Sydney, 2006, NSW, Australia.
Clarke
Stephen J
SJ
McLachlan
Andrew J
AJ
Blair
Elaine Y L
EY
Rivory
Laurent P
LP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel