Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion

Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1 -h intravenous infusion ata dose level of 100 mg/m(2) with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a th ree-compartment model. The mean area under the curve (AUC) for docetaxel wa s 3.1 +/- 0.9 h . mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). The re was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5-30 min after the end of the infusion. The cyclized oxazolidinedione metab olite M4 was most frequently present and was detected in 8 out of 24 patien ts with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regres sion analysis was performed to predict M4 docetaxel metabolism. In the fina l model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and p ercentage decrease in neutrophil count in this study. Three patients with h igh M4 concentrations in plasma during course 1 suffered from most pronounc ed fluid retention (grade 2-3) after two to five courses.