Population pharmacokinetics of weekly docetaxel in patients with advanced cancer

ABSTRACT

Aims  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 α₁-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/t_max). 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/t_max (erythromycin breath test parameter) and several of the liver function enzymes and CL was best described by the equation; CL = 21.51 + 217 (1/t_max) − 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.