Clinical pharmacokinetics of docetaxel.

Abstract

Docetaxel (Taxotere), a semi-synthetic analog of paclitaxel (Taxol), is a promoter of microtubule polymerization leading to cell cycle arrest at G2/M, apoptosis and cytotoxicity. Docetaxel has significant activity in breast, non-small-cell lung, ovarian and head and neck cancers. Docetaxel has undergone phase I study in a number of schedules, including different infusion durations and various treatment cycles. Doses studied in adults have ranged from 5 to 145 mg/m2 and those in children from 55 to 235 mg/m2. The most frequently used regimen in adults is 100 mg/m2 every 3 weeks. A 1-hour infusion every 3 weeks has been favoured in phase II and III studies, and the disposition of docetaxel after such treatment is best described by a 3 compartment model with alpha, beta and gamma half-lives of 4.5 minutes, 38.3 minutes and 12.2 hours, respectively. The disposition of docetaxel appears to be linear, the area under the plasma concentration-time curve (AUC) increasing proportionately with dose. Docetaxel is widely distributed in tissues with a mean volume of distribution of 74 L/m2 after 100 mg/m2, every 3 weeks. The mean total body clearance after this schedule is approximately 22 L/h/m2, principally because of hepatic metabolism by the cytochrome P450 (CYP)3A4 system and biliary excretion into the faeces. Renal excretion is minimal (< 5%). Docetaxel is > 90% bound in plasma. Population pharmacokinetic studies of docetaxel have demonstrated that clearance is significantly decreased with age, decreased body surface area, increased concentrations of alpha 1-acid glycoproteinand albumin. Importantly, patients with elevated plasma levels of bilirubin and/or transaminases have a 12 to 27% decrease in docetaxel clearance and should receive reduced doses. Although docetaxel is metabolised by CYP3A4, phase I combination studies have not shown major evidence of significant interaction between docetaxel and other drugs metabolised by the same pathway. Nevertheless, care should be taken with the use of known CYP3A4 inhibitors such as erythromycin, ketoconazole and cyclosporin. Conversely, increased doses may be required for patients receiving therapy known to induce this cytochrome (e.g. anticonvulsants). Perliminary data suggest the erythromycin breath test, an indicator of CYP3A4 function, is a predictor of toxicity after treatment with docetaxel. Such methodologies may eventually enable clinicians to individualise doses of docetaxel for patients with cancer.