Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic Properties

Paclitaxel promotes the formation of microtubules from tubulin dimers as well as microtubule assembly; it stabilises the microtubules and prevents their depolymerisation. The suppression of microtubule depolymerisation prevents their intracellular reorganisation and leads to aggregation of free tubulin units. The stabilised and dysfunctional microtubules inhibit the formation of a new spindle apparatus and prevent a new regular mitosis. Paclitaxel thus inhibits the cell cycle in the G2 and M phases.

Tumour cells can also develop resistance to paclitaxel: In cell lines of ovarian cancer a secondary resistance to paclitaxel in cells with modified alpha- and beta-tubulin could be shown.

The second resistance mechanism is associated with the MDR gene. P- glycoprotein, a phosphorylated glycoprotein of the plasma membrane, acts as an efflux pump, thus keeping intracellular concentration of the drug below toxicity level.

In a large randomised controlled study, the safety and efficacy of paclitaxel (135 mg/m2/24h) followed by cisplatin (75 mg/m2) versus 750 mg/m2 of cyclophosphamide and 75 mg/m2 of cisplatin (GOG-111/B-MS CA 139-022) for first- line chemotherapy of ovarian cancer was evaluated. This study comprised more than 400 patients with untreated stage III/IV ovarian cancer, residual tumours >1 cm after laparotomy or metastatic ovarian cancer. The paclitaxel arm showed a significant increase in median progression-free survival (>3.5 months) and median overall survival (>11 months), while the (severe) toxicity potential was similar in both arms.

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 appetite is improved and show a clear disadvantage of paclitaxel with respect to the occurrence of peripheral neuropathy (p>0.008).
In a study of non-small cell lung cancer therapy in 599 patients with advanced and metastatic NSCLC publicised by the Eastern Cooperative Oncology Group (ECOG), two dosage regimens of paclitaxel (135 and 250 mg/m2 as a 24-hour infusion) plus cisplatin (75 mg/m2) were compared with etoposide (100 mg/m2) plus cisplatin (75 mg/m2). Responses were 27% and 32% in the paclitaxel combination groups compared to 12% in the etoposide-plus-cisplatin group. Superior overall survival was observed in the groups with combined paclitaxel regimens (9.9 months vs.
7.6 months). Granulocytopenia, myalgia, neurotoxicity and possibly also cardiotoxicity were more common in the paclitaxel-plus-cisplatin group than in the etoposide-plus- cisplatin group.

Pharmacokinetic Properties

5.2 Pharmacokinetic Properties

Intravenous administration of paclitaxel demonstrates a biphasic plasma clearance.

Plasma binding is extensive and ranges from 89% to 98% (in vitro studies, at concentrations of 0.1-50 μg/l).

The steady-state volume of distribution of paclitaxel ranges from 198 to 688 l/h/m2, indicating extensive extravascular and/or tissue binding. A half-life of 3-52 hours has been registered.
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 3-53 hours has been registered. The mean non-compartment-dependent values for overall body clearance range from 11.6 to 24 l/h/m2.
Overall clearance of the drug from the body seems to decrease with higher paclitaxel concentrations in the plasma.

Increasing dose levels in a three-hour infusion exhibit non-linear pharmacokinetics. Increasing dosage by 30% from 135 mg/m2 to 175 mg/m2 resulted in an increase in Cmax and AUC0 values by 75% and 81%, respectively. Intraindividual variability after systemic administration was minimal. No evidence of a cumulative effect of paclitaxel in several treatment courses has been found.

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 13% of the administered dose, indicating pronounced non-renal clearance. Paclitaxel is assumed to be primarily eliminated through the hepatic metabolism (generally through cytochrome P450 enzymes). After administration of radioactively marked paclitaxel, mean recovery of the radioactive substance in the faeces is 26% as 6a-hydroxypaclitaxel, 2% as 3'-p-hydroxypaclitaxel and 6% as 6a, 3'-p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites is catalysed by the isoenzymes CYP2C8 and CYP3A4. 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 who received 135 mg/m2 of paclitaxel as a three-hour infusion were similar to the values exhibited in non-dialysis patients.