Unitaxel Mechanism of Action

Pharmacology: Pharmacodynamics: Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Pharmacokinetics: Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations. The pharmacokinetics of paclitaxel were determined following 3 and 24 hour infusions at doses of 135 and 175 mg/m². Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 l/hr/m²; total body clearance appeared to decrease with higher plasma concentrations of paclitaxel. Mean steady-state volume of distribution ranged from 198 to 688 l/m², indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m² to 175 mg/m², the C_max and AUC_→∞ values increased 75% and 81%, respectively.
Following an intravenous dose of 100 mg/m² given as a 3-hour infusion to 19 KS patients, the mean C_max was 1,530 ng/ml (range 761-2,860 ng/ml) and the mean AUC 5,619 ng.hr/ml (range 2,609-9,428 ng.hr/ml). Clearance was 20.6 l/h/m² (range 11-38) and the volume of distribution was 291 l/m² (range 121-638). The terminal elimination half-life averaged 23.7 hours (range 12-33).
Intrapatient variability in systemic paclitaxel exposure was minimal. There was no evidence for accumulation of paclitaxel with multiple treatment courses.
In vitro studies of binding to human serum proteins indicate that 89-98% of medicinal product is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of paclitaxel.
The disposition of paclitaxel has not been fully elucidated in humans. Mean values for cumulative urinary recovery of unchanged drug have ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. Paclitaxel appears to be metabolised primarily by cytochrome P450 enzymes. Following administration of a radiolabelled paclitaxel, an average of 26, 2 and 6% of the radioactivity was excreted in the faeces as 6α-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel, and 6α-3'-p-dihydroxy-paclitaxel, respectively. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 respectively. The effect of renal or hepatic dysfunction on the disposition of paclitaxel following a 3-hour infusion has not been investigated formally. Pharmacokinetic parameters obtained from one patient undergoing haemodialysis who received a 3-hour infusion of paclitaxel 135 mg/m² were within the range of those defined in non-dialysis patients.
In clinical trials where paclitaxel and doxorubicin were administered concomitantly, the distribution and elimination of doxorubicin and its metabolites were prolonged. Total plasma exposure to doxorubicin was 30% higher when paclitaxel immediately followed doxorubicin than when there was a 24-hour interval between medicinal product.
For use of paclitaxel in combination with other therapies, please consult the Summary of Product Characteristics of cisplatin, doxorubicin or trastuzumab for information on the use of these medicinal products.