Clipax Mechanism of Action

Antineoplastic.
Pharmacology: Pharmacodynamics: Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerisation. This stability inhibits the 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.
In first-line treatment of ovarian cancer, the safety and efficacy of Paclitaxel were evaluated in two major randomized controlled trials (compared with Cyclophosphamide 750 mg/m² + Cisplatin 75 mg/m² therapy).
In the Intergroup trial (EMS CA 139-209), over 650 patients with stage IIb-c, III or IV primary ovarian cancer had administered to them a maximum of 9 courses of treatment with Paclitaxel (175 mg/m² over a 3-hour period) followed by Cisplatin (75 mg/m²) or control treatment. In another major study (GOG 111/B-MS CA 139-022), a maximum of 6 courses of treatment with Paclitaxel were administered (135 mg/m², during a 24-hour infusion) combined with Cisplatin (75 mg/m²) or control treatment; the trial involved over 400 patients with stage III or IV primary ovarian cancer with a >1 cm residual tumour after staging laparotomy, or with distant metastases. While the two different posologies were not compared with each other directly, in both trials the patients on Paclitaxel and Cisplatin had a significantly higher response rate, later onset of progression of disease and longer survival time than the patients on standard therapy. Increased neurotoxicity, arthralgia/myalgia but reduced myelosuppression were observed in advanced ovarian cancer patients administered 3-hour infusion of Paclitaxel/Cisplatin as compared to patients who received Cyclophosphamide/Cisplatin.
In the adjuvant treatment of breast carcinoma, 3121 patients with node positive breast carcinoma were treated with adjuvant Paclitaxel therapy or no chemotherapy following four courses of Doxorubicin and Cyclophosphamide (CALGB 9344, BMS CA 139-223). Median follow-up was 69 months. Overall, Paclitaxel patients had a significant reduction of 18% in the risk of disease recurrence relative to patients receiving AC alone (p = 0.0014), and a significant reduction of 19% in the risk of death (p = 0.0044) relative to patients receiving AC alone. Retrospective analyses show benefit in all patient subsets. In patients with hormone receptor negative/unknown tumours, reduction in risk of disease recurrence was 28% (95%CI, 0.59-0.86). In the patient subgroup with hormone receptor positive tumours, the risk reduction of disease recurrence was 9% (95%CI, 0.78-1.07). However, the design of the study did not investigate the effect of extended AC therapy beyond 4 cycles. It cannot be excluded on the basis of this study alone that the observed effects could be partly due to the difference in duration of chemotherapy between the two arms (AC 4 cycles, AC + Paclitaxel 8 cycles). Therefore, adjuvant treatment with Paclitaxel should be regarded as an alternative to extended AC therapy.
In a second large clinical study in adjuvant node positive breast cancer with a similar design, 3060 patients were randomized to receive or not four courses of Paclitaxel at a higher dose of 225 mg/m² following four courses of AC (NSABP B-28, BMS CA139-270). At a median follow-up of 64 months, Paclitaxel patients had a significant reduction of 17% in the risk of disease recurrence relative to patients who received AC alone (p = 0.006). Paclitaxel treatment was associated with a reduction in the risk of death of 7% (95%CI 0.78-1.12). All subset analyses favoured the Paclitaxel arm. In this study, patients with hormone receptor positive tumor had a reduction in the risk of disease recurrence of 23% (95%CI 0.6-0.92), in the patient subgroup with hormone receptor negative tumour the risk reduction of disease recurrence was 10% (95%CI 0.7-1.11).
In the first-line treatment of metastatic breast cancer, the efficacy and safety of Paclitaxel were evaluated in two pivotal, phase III, randomized controlled open-label trials.
In the first study (BMS CA139-278), the combination of bolus Doxorubicin (50 mg/m²) followed after 24 hours by Paclitaxel (220 mg/m² by 3-hour Infusion) (AT), was compared versus standard FAC regimen (5-FU 500 mg/m², Doxorubicin 50 mg/m², Cyclophosphamide 500 mg/m²), both administered every three weeks for eight courses. In this randomized study, 267 patients with metastatic breast cancer, who had either received no prior chemotherapy or only non-anthracycline chemotherapy in the adjuvant setting, were enrolled. Results showed a significant difference in time to progression for patients receiving AT compared to those receiving FAC (8.2 vs. 6.2 months; p = 0.029). The median survival was in favour of Paclitaxel/Doxorubicin vs. FAC (23.0 vs 18.3 months; p = 0.004). In the AT and FAC treatment arm 44% and 48% respectively received follow-up chemotherapy which included taxanes in 7% and 50% respectively. The overall response rate was also significantly higher in the AT arm compared to the FAC arm (68% vs. 55%). Complete responses were seen in 19% of the Paclitaxel/Doxorubicin arm patients vs. 8% of the FAC arm patients. All efficacy results have been subsequently confirmed by a blinded independent review.
In the second study, the efficacy and safety of the Paclitaxel and Trastuzumab combination was evaluated in a planned subgroup analysis (metastatic breast cancer patients who formerly received adjuvant anthracyclines) of the study HO648g. The efficacy of Trastuzumab in combination with Paclitaxel in patients who did not receive prior adjuvant anthracyclines has not been proven. The combination of Trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) and Paclitaxel (175 mg/m²) 3-hour infusion, every three weeks was compared to single-agent Paclitaxel (175 mg/m²) 3-hour infusion, every three weeks in 188 patients with metastatic breast cancer overexpressing HER2 (2+ or 3+ as measured by immunohistochemistry), who had previously been treated with anthracyclines. Paclitaxel was administered every three weeks for at least six courses while Trastuzumab was given weekly until disease progression. The study showed a significant benefit for the Paclitaxel/Trastuzumab combination in terms of time to progression (6.9 vs. 3.0 months), response rate (41% vs. 17%), and duration of response (10.5 vs. 4.5 months) when compared to Paclitaxel alone. The most significant toxicity observed with the Paclitaxel/Trastuzumab combination was cardiac dysfunction.
In the treatment of very advanced non-small cell lung cancer, the combination of 175 mg/m² of Paclitaxel and 80 mg/m² of Cisplatin (given after Paclitaxel) has been studied in two phase III trials (367 patients on Paclitaxel therapy). Both trials were randomized. In one of the trials the control group received Cisplatin (100 mg/m²) and in another, 100 mg/m² of Teniposide followed thereafter by 80 mg/m² of Cisplatin (367 patients in the control group). The results of both trials were similar. There were no significant differences between the Paclitaxel therapy and control therapy regarding mortality, primary end event (the median survival time in the Paclitaxel groups were 8.1 and 9.5 months, and in the control groups 8.6 and 9.9 months). There were no significant differences in the median time of progression of the disease between the therapies either. The benefit was significant regarding clinical response. Studies on the quality of life indicate that the lack of appetite caused by combination treatment containing Paclitaxel is smaller, but they also indicate an increased incidence of peripheral neuropathy (p<0.008) with combination treatment.
In the treatment of AIDS-related KS, the efficacy and safety of Paclitaxel were investigated in a non-comparative study in patients with advanced KS, previously treated with systemic chemotherapy. The primary end-point was best tumour response. Of the 107 patients, 63 were considered resistant to liposomal anthracyclines. This subgroup is considered to constitute the core efficacy population. The overall success rate (complete/partial response) after 15 cycles of treatment was 57% (confidence interval (CI) 44 - 70%) in liposomal anthracycline-resistant patients. Over 50% of the responses were apparent after the first 3 cycles. In liposomal anthracycline-resistant patients, the response rates were comparable for patients who had never received a protease inhibitor (55.6%) and those who received one at least 2 months prior to treatment with Paclitaxel (60.9%). The median time to progression in the core population was 468 days (95% CI 257-not estimable). Median survival could not be computed, but the lower 95% bound was 617 days in core patients.
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. The mean half-life was between 3.0 and 52.7 hours, and the mean non-compartmentally derived value for total body clearance was between 11.6 and 24.0 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 patient 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 feces as a 6α-hydroxypaclitaxel. 2% as 3'p-dihydroxypaclitaxel and 6% as 6α-3'p-dihydroxypaclotaxel, 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 impairment 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 non-dialysis 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 KS patients, the mean Cmax 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).
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.