Daxotel Mechanism of Action

Pharmacology: Pharmacodynamics: Docetaxel is an antineoplastic agent acting at the microtubules. Docetaxel enhances polymerization of the tubulin into stable microtubules and inhibits their depolymerization. This induces the formation of stable microtubule bundles leading to cell death.
Pharmacokinetics: The pharmacokinetic studies on Docetaxel reveal that there is no schedule dependence of Docetaxel disposition. The area under the curve (AUC) was dose proportional following doses of 70 mg/m² to 115 mg/m² with infusion times of 1 to 2 hours. At the highest clinical doses level examined in the 1-h infusion schedule every 3 weeks, docetaxel disposition was triphasic, with a terminal half-life of 11 to 18 h and a plasma clearance of 16 to 21 l/h/m². The half lives for α, β and γ phases were 4 min, 36 min and 11.1 hours respectively while systemic clearance was 21 l/h/m².
The major route of elimination of Docetaxel and its metabolites is fecal through which about 80% of the drug is excreted. About 5% excretion takes place from urine. Only a minor fraction of administered drug is excreted as the parent drug. Docetaxel metabolism involves the isoenzymes of the cytochrome P450-3A subfamily and more than 95% of Docetaxel is bound to plasma proteins.
Toxicology: Preclinical safety data: Carcinogenicity studies with Docetaxel have not been performed.
Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60^th to 1/15^th the recommended human dose on a mg/m² basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.
Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50^th the recommended human dose on a mg/m² basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3^rd and 1/15^th the recommended human dose on a mg/m² basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels