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Pharmacological Classification: Antineoplastic. ATC Code: L01C D01.
Pharmacology: Pharmacodynamics: Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability inhibits normal dynamic reorganization of the microtubule network, which 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 determined following 3 and 24 hour infusions at doses levels of 135 and 175 mg/m2 were determined in an ovarian cancer patients. The mean half-life was between 3 and 52.7 hours, and the mean non-compartmentally derived value for total body clearance was between 11.6 and 24 L/hr. /m2. The total body clearance appeared to decrease with higher plasma concentrations. The mean steady-state volume of distribution was between 198 and 688 L/m2, indicating extensive extravascular distribution and/or tissue binding. Dose increases associated with the 3 hour infusion resulted in non-linear pharmacokinetics. When the dose increased by 30% from 135 mg/m2 to 175 mg/m2, the maximum plasma concentration (Cmax) increased by 75% and the area under the plasma concentration time curve (AUC0-∞) by 81%. The variation of systemic paclitaxel exposure in the same patients was found to be minimal. No signs of cumulative effects were found for paclitaxel in association with multiple treatment courses.
In vitro studies of serum protein binding indicate that 89-98% of paclitaxel is bound to proteins. Cimetidine, ranitidine, dexamethasone, or diphenhydramine were not found to affect the protein binding of paclitaxel.
The distribution and metabolism of paclitaxel in humans has not been fully investigated. The cumulative excretion of unchanged paclitaxel in the urine has been between 1.3% and 12.6% of the dose on average, which is an indication of extensive non-renal clearance. Hepatic metabolism and biliary clearance are possibly the principal mechanisms for elimination of paclitaxel. Paclitaxel is primarily metabolized by the action of CYP450 enzyme. An average of 26% of the radioactively marked dose of paclitaxel was eliminated in the faeces as 6α-hydroxypaclitaxel, 2% as 3'p-dihydroxypaclitaxel and 6% as 6α-3'p-dihydroxypaclitaxel. 6α-hydroxypaclitaxel is formed by the effect of CYP2C8, 3'p-hydroxypaclitaxel by CYP3A4 and 6α-3'p-dihydroxypaclitaxel by CYP2C8 and CYP3A4. The effect of renal or hepatic insufficiency on the elimination of paclitaxel after 3 hour infusions has not been studied. The pharmacokinetic parameters of a patient on haemodialysis were of values similar to those of nondialysis patients when the administration rate was 135 mg/m2 of paclitaxel as a 3 hour infusion. Following an intravenous dose of 100 mg/m2 given as a 3 hour infusion to 19 Kaposi's Sarcoma patients; the mean Cmax was 1530 ng/mL (range 761-2860 ng/mL) and the mean AUC 5619 ng·hr/mL (range 2609-9428 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).
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 drugs.
Toxicology: Preclinical safety data: Administration prior to or during mating produced impairment of fertility in male and female rats. Additionally, paclitaxel caused reduced fertility and reproductive indices, and increased embryo-and fetotoxicity. The carcinogenic potential of paclitaxel has not been studied. However, paclitaxel is a potential carcinogenic and genotoxic agent based on its pharmacodynamic mechanisms of action. Paclitaxel has been shown to be mutagenic in both in vitro and in vivo mammalian test systems.
