Ebetaxel Mechanism of Action





Firma Vai Hong
Full Prescribing Info
Pharmacotherapeutic Group: Cytotoxic agent. ATC Code: L01C D01.
Pharmacology: Pharmacodynamics: Paclitaxel is a new anti-microtubular agent which promotes the formation of microtubules from tubulin dimers and stabilises the microtubules by preventing depolymerisation. This stability leads to a suppression of the normal dynamic reorganisation of the microtubule network that is essential for the vital cell functions in interphase and mitosis. Paclitaxel additionally induces the formation of abnormal rows or bundles of microtubules throughout the entire cell cycle and multiple star-like microtubule structures during mitosis.
The safety and efficacy of paclitaxel for first-line chemotherapy of ovarian cancer was evaluated in two large randomised controlled trials (versus 750 mg/m2 of cyclophosphamide and 75 mg/m2 of cisplatin). In the cross-group trial (B-MS CA 139-209) more than 650 patients with primary stage IIb-c, III or IV ovarian cancer received a maximum of 9 therapy courses with paclitaxel (175 mg/m2 over 3 hours), followed by cisplatin (75 mg/m2), or placebo. The second important trial (GOG 111/B-MS CA 139-022) comprised more than 400 patients with untreated stage III/IV ovarian cancer and residual tumours >1 cm after laparotomy, or peripheral metastases. They received a maximum of 6 therapy cycles with either paclitaxel (135 mg/m2 over 24 hours), followed by cisplatin (75 mg/m2) or a placebo. Although the two different dosages of paclitaxel were not directly compared with each other, in both trials the response rate of patients receiving paclitaxel-plus-cisplatin was significantly higher and progression-free survival and overall survival significantly prolonged in comparison to standard therapy.
In patients with advanced ovarian cancer receiving paclitaxel as a three-hour infusion, followed by cisplatin, the incidence of neurotoxicity and arthralgia/myalgia was increased, but the incidence of myelosuppression reduced, when compared to patients treated with cyclophosphamide-plus-cisplatin.
The efficacy and safety of paclitaxel in combination with Herceptin for first-line therapy of metastatic breast cancer were evaluated in a planned sub-group analysis of trial HO648g (patients with metastatic breast cancer previously receiving supportive treatment with anthracyclines). Efficacy of Herceptin in combination with paclitaxel in patients not previously undergoing supportive treatment with anthracyclines was not evaluated. The combination of trastuzumab (loading dose of 4 mg/kg, followed by 2 mg/kg weekly) and paclitaxel (175 mg/m2) as a three-hour infusion every 3 weeks was compared with single-use paclitaxel (175 mg/m2) as a three-hour infusion every 3 weeks in 188 patients with metastatic breast cancer overexpressing HER-2 (2+ or 3+; immunohistochemical measurement) and previously receiving anthracycline therapy. Paclitaxel was administered every 3 weeks for at least 6 therapy courses, trastuzumab was applied weekly until progression of the disease. The study demonstrated a significant benefit of paclitaxel-plus-trastuzumab compared to single-agent paclitaxel in terms of progression-free survival (6.9 vs. 3.0 months), response rate (41% vs. 17%) and duration of response (10.5 vs. 4.5 months).
Cardiac function impairment was found to be the most important toxic reaction in patients receiving paclitaxel-plus-trastuzumab (see Adverse Reactions).
For the treatment of advanced non-small-cell lung cancer, a therapy regimen consisting of 175 mg/m² of paclitaxel, followed by 80 mg/m² of cisplatin, was evaluated in two phase III trials (367 patients received paclitaxel). Both were randomised studies, one drawing a comparison to 100 mg/m² of cisplatin, the other to 100 mg/m² of teniposide, followed by 80 mg/m² of cisplatin (367 patients in the control group). Both studies exhibited similar results. With regard to mortality as the primary end point, no significant difference between the paclitaxel arm and the control arm was detected (median survival was 8.1 and 9.5 months in the paclitaxel group and 8.6 and 9.9 months in the control group). Likewise, there was no significant difference in progression-free survival. A significant benefit in clinical response was observed. Data on paclitaxel therapy conclude that the quality of life as regards loss of appetite is improved and show a clear disadvantage of paclitaxel with respect to the occurrence of peripheral neuropathy (p >0.008).
Pharmacokinetics: Intravenous administration of paclitaxel demonstrates a biphasic plasma clearance.
The pharmacokinetic data were derived after three-hour and 24-hour infusions of 135 mg/m2 and 175 mg/m2.
A mean terminal elimination half-life of 3-52.7 hours has been registered. The mean non-compartment-dependent values for overall body clearance range from 11.6 o 24 l/h/m2. Overall clearance of the drug from the body seems to decrease with higher paclitaxel concentrations in the plasma.
The steady-state volume of distribution of paclitaxel ranges from 198 to 688 l/h/m2, indicating extensive extravascular and/or tissue binding.
Increasing dose levels in a three-hour infusion exhibit non-linear pharmacokinetics. Increasing dosage by 30% from 135 mg/m2 to 175 mg/m2 results in an increase in Cmax and AUC0 values by 75% and 81%, respectively.
Intraindividual variability after systemic administration is minimal. No evidence of a cumulative effect of paclitaxel in several treatment courses has been found.
In vitro studies investigating the binding kinetics of paclitaxel to human plasma proteins have shown extensive plasma binding ranging from 89% to 98%. Cimetidine, ranitidine, dexamethasone or diphenhydramine had no impact on the protein binding capacity of paclitaxel.
The elimination pathways of paclitaxel in humans are currently not fully known.
The mean values for cumulative urinary recovery of unchanged paclitaxel range from 1.3 to 12.6% of the administered dose, indicating pronounced non-renal clearance. Paclitaxel is assumed to be primarily metabolised in the liver and excreted in the bile. Paclitaxel seems to be metabolised mainly through cytochrome P450 enzymes. After administration of radioactively marked paclitaxel, mean recovery of the radioactive substance in the faeces is 26% as 6α-hydroxy paclitaxel, 2% as 3'-p-hydroxy paclitaxel and 6% as 6α,3'-p-dihydroxy paclitaxel. The formation of these hydroxylated metabolites is catalysed by the iso-enzymes CYP2C8, -3A4 (-2C8 and -3A4). There are no current data on elimination after three-hour infusion of paclitaxel in patients with hepatic and renal infusion impairment. The pharmacokinetic parameters of a patient undergoing haemodyalysis who received 135 mg/m2 of paclitaxel as a three-hour infusion were similar to the values exhibited in non-dialysis patients.
If paclitaxel is to be combined with other therapeutic agents, please consult the prescribing information (SPC) for cisplatin- or trastuzumab-containing medicinal products to learn more about the use of these agents.
Toxicology: Preclinical safety data: Studies on the carcinogenic potential of paclitaxel have not been performed. Due to its pharmacodynamic reaction mechanism, however, paclitaxel is regarded as potentially carcinogenic and genotoxic.
Both in vitro and in vivo studies demonstrate that paclitaxel has a mutagenic effect on mammalian cells.
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