Taxol Mechanism of Action

ATC Code: L01C D01.
Pharmacology: Pharmacodynamics: Mechanism of Action: Paclitaxel is an antimitotic agent of the taxane class. Paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for the interphase and parts of mitotic function.
During mitosis, paclitaxel furthermore induces abnormal bundles of microtubules and multiple asters of microtubules are formed.
Clinical Efficacy: Primary treatment of ovarian carcinoma: The safety and efficacy of Taxol for the primary treatment of ovarian carcinoma (with Taxol infusion over 3 and 24 hours, respectively) has been investigated in two randomized controlled studies (vs. cyclophosphamide 750 mg/m² / cisplatin 75 mg/m²).
In the Intergroup study (B-MS CA 139-209), more than 650 patients with FIGO stage IIb-c, III or IV primary ovarian carcinoma were included. The patients received a maximum of 9 treatment courses of Taxol (175 mg/m² over 3 hours), followed by cisplatin (75 mg/m²) or the control treatment cyclophosphamide/cisplatin.
The median time to progression was 15.3 months vs. 11.5 months, and median survival was 35.6 months vs. 25.9 months.
The second study (GOG-111/B-MS CA 139-022) evaluated more than 400 patients with FIGO stage III/IV primary ovarian carcinoma, with a >1 cm residual carcinoma following laparotomy, or with metastatic ovarian carcinoma. The patients received a maximum of 6 courses of Taxol (135 mg/m² over 24 hours), followed by cisplatin (75 mg/m²) or the control treatment cyclophosphamide/cisplatin.
The median time to progression was 16.6 months vs. 13.0 months, and median survival was 35.5 vs. 24.2 months.
In patients with advanced ovarian carcinoma treated with Taxol/cisplatin (3-hour infusion), increased neurotoxicity and arthralgia/myalgia but reduced myelosuppression, was observed as compared to cyclophosphamide/cisplatin treatment.
Treatment of non-small cell lung carcinoma: The safety and efficacy of Taxol in the treatment of non-small cell lung carcinoma has been evaluated in patients without previous chemotherapy in four phase II trials (n=224) and in two randomized phase III trials (n=931).
In the phase III trials, Taxol (in combination with 75 or 80 mg/m² cisplatin) was statistically significantly better as compared to treatment with etoposide or teniposide associated with cisplatin. The time to progression of the disease was between 4.3 and 5.1 months in the Taxol group, with a median survival of 9.3-10.0 months, and a one year survival rate of 36-41%. A significant improvement of quality in life of the persons treated with Taxol was observed in both trials.
Primary treatment of metastatic breast carcinoma, in combination with trastuzumab: Refer to information for healthcare professionals on Herceptin (trastuzumab).
Secondary treatment of metastatic breast carcinoma resistant to standard therapy: In a randomized multicenter phase III study, patients with relapse following adjuvant treatment or following premedication with combined chemotherapy received Taxol at a dosage of 175 mg/m² or 135 mg/m², administered as a 3-hour infusion. The overall response rate for the 454 evaluable patients was 26% (complete response in 17 cases, partial response in 99 cases).
The median duration of response, measured from the first day of treatment, was 8.1 months. The median time to progression was 3.0 months for patients with a dosage of 135 mg/m² and 4.2 months for patients with a dosage of 175 mg/m², respectively. Overall, the median survival (n=471) was 11.7 months.
Adjuvant treatment of breast carcinoma: In an open, randomized American intergroup study for adjuvant treatment of breast carcinoma in node positive patients, 3121 subjects with stage I-III were either treated with 4 courses of Taxol 175 mg/m² (T) following AC treatment (doxorubicin + cyclophosphamide) or with AC alone. Hormone receptor positive patients received tamoxifen additionally. The interim analysis of this study with a median duration of treatment of 52.2 months showed significantly better results on AC plus Taxol treatment. The advantage of additional Taxol treatment was 13% in DFS (hazard ratio 0.87) and 14% in OS (hazard ratio 0.86) while the recurrence rates were low in both treatment arms: 469/1551 (32.0%) for AC and 432/1570 (27.5%) for AC plus Taxol. It was only in patients with estrogen receptor negative tumors (without tamoxifen treatment) that additional Taxol treatment was highly significant with a hazard ratio of 0.71 in DFS (95% CI 0.58-0.88; p<0.001). In those patients with estrogen receptor positive tumors, who also received tamoxifen (i.e. in two thirds of the study population), there was no difference between AC and AC plus Taxol (hazard ratio in DFS 1.0). Furthermore, no significant differences with Taxol were observed in patients with small tumor (<2 cm, T1) or in high risk patients with 10 or more positive lymph nodes (LN) or tumors >5 cm (T3).
Pharmacokinetics: The pharmacokinetic parameters were determined following 3-hour and 24-hour intravenous infusion, respectively, at paclitaxel doses of 135 and 175 mg/m². Intrapatient variability in paclitaxel exposure was minimal. Pharmacokinetics, when short infusion was used, were determined primarily by Cremophor EL.
With the 3-hour infusion, increasing doses resulted in non-linear pharmacokinetics.
With the 24-hour infusion, kinetics are almost linear with dosage.
With the 3-hour infusion at 175 mg/m², C_max is 10-fold and AUC 3-fold higher than with the 24-hour infusion at 135 mg/m².
Distribution: The distribution of paclitaxel has not been fully elucidated in humans. Mean steady-state volume of distribution ranged from 198 to 688 L/m², indicating extensive tissue distribution and/or tissue binding.
In vitro binding studies indicate that 89-98% of drugs are bound to plasma proteins. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect protein binding.
There was no evidence for accumulation of paclitaxel with multiple treatment courses.
Metabolism: Paclitaxel is metabolized primarily by cytochrome P450 enzymes. 6α-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6α-3'-p-dihydroxypaclitaxel have been identified as primary metabolites. The formation of these metabolites is catalyzed by CYP2C8 and CYP3A4. The major metabolic pathway is metabolization to 6α-hydroxypaclitaxel via CYP2C8. Also refer to Interactions.
Elimination: Following intravenous administration, paclitaxel plasma levels exhibit a biphasic decline. Hepatic metabolism and biliary clearance are the two important mechanisms of elimination. The mean terminal half-life ranged from 3.0 to 52.7 hours, and the mean values for total body clearance ranged from 11.6 to 24.0 L/hr/m². Total body clearance appeared to decrease with increasing plasma concentrations of paclitaxel. Mean values for cumulative urinary recovery of unchanged drug have ranged from 1.3 to 12.6%, indicating extensive non-renal clearance.
Kinetics in Special Clinical Situations: Impaired renal function: The effect of reduced renal function on the disposition of paclitaxel following a 3-hour infusion has not been investigated yet. Paclitaxel is not dialyzable.
Impaired hepatic function: The pharmacokinetics of paclitaxel has been investigated in 35 patients with increased bilirubin levels. At bilirubin levels between 1 and 2x ULN, the AUC was increased however without toxicity increase; at bilirubin levels >2x ULN, an increased myelotoxicity has been observed.
Toxicology: Preclinical Data: There are no carcinogenicity studies. Based on its mechanism of action, paclitaxel is a potential carcinogenic and genotoxic agent. Paclitaxel has been shown to be mutagenic in animal studies (in vitro and in vivo).