Pharmacokinetic and pharmacodynamic properties of docetaxel: results of phase I and phase II trials.

Abstract

The pharmacokinetics of docetaxel as investigated in Phase I and Phase II trials are discussed. Phase I trials have shown that docetaxel exhibits linear pharmacokinetics consistent with a three-compartment model. Population pharmacokinetic and pharmacodynamic analysis of the results of 22 nonrandomized Phase II trials with nonlinear mixed-effects modeling showed that the interpatient variability of docetaxel pharmacokinetics is mainly related to body surface area and hepatic function. The effect of body surface area on clearance does not present a problem, since the dose of docetaxel is adjusted for body size. However, patients with impaired liver function are at increased risk of serious adverse effects (febrile neutropenia, severe infections, severe stomatitis, and toxic death) during treatment with docetaxel 100 mg/ m2. Patients with impaired liver function should receive a reduced dose (75 mg/m2). The presence of liver metastases without impaired liver function had no effect on docetaxel's clearance or safety, suggesting that a dose of 100 mg/m2 is well tolerated in such patients. Docetaxel pharmacokinetics and pharmacodynamics determined in Phase I and Phase II trials indicate a need to adjust the dosage for body surface area and liver function.