Paclib Mechanism of Action

Pharmacological Category/Classification: Antineoplastic (Taxane).
Pharmacology: Pharmacodynamics: 5 mL & 16.67 mL: Mechanism of Action: Paclitaxel is a member of the taxane group of anticancer drugs. It is a potent inhibitor of tumor cell replication, blocking cells in the late G2 to M phase of the cell cycle. Paclitaxel promotes abnormal assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability disrupts the normal dynamic reorganization of the microtubule network which is essential for mitosis/cell replication. Paclitaxel also induces abnormal arrays of microtubules throughout the cell cycle and multiple esters of microtubules during mitosis, further disrupting cell function.
43.4 mL: Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that 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: 5 mL & 16.67 mL: Paclitaxel exhibits nonlinear, dose-dependent pharmacokinetics, especially when the drug is administered over short infusion periods (e.g., 3 hours). Relatively small changes in dose may lead to large changes in peak plasma concentrations and total drug exposure due to the nonlinearity of paclitaxel's pharmacokinetics. Paclitaxel's peak plasma concentration and area under the curve (AUC) exhibit interindividual variation after intravenous (IV) administration. Peak plasma concentrations increase during continuous IV administration of paclitaxel and decline immediately after infusion.
Paclitaxel is widely distributed in body fluids and tissues. The dose and duration of infusion affect paclitaxel's volume of distribution. After a 24-hour infusion, the mean apparent volume of distribution at steady state ranged from 227 to 688 L/m² in patients with advanced ovarian cancer. The steady-state volume of distribution ranged from 18.9 to 260 L/m² at a dose of 200 to 500 mg/m² in children with solid tumors or refractory leukemia. Approximately 88 to 98% of paclitaxel is protein-bound. It is detected in the ascitic fluid after IV infusion and does not readily penetrate the CNS.
Plasma concentrations of paclitaxel fall in a biphasic manner with a distribution half-life of 0.34 hour. Average elimination half-life is 5.8 hours in adults with malignancy after 6 to 24 hours IV infusion. After a 3-hour IV infusion of 175 mg/m², the average distribution half-life and elimination half-life is 0.27 hour and 2.33 hours, respectively. Paclitaxel is metabolized extensively in the liver by cytochrome P450 (CYP3A4 may play a minor role) to its major metabolite, 6α-hydroxypaclitaxel. It is excreted principally in the feces via biliary excretion. Less than 10% of the administered dose is excreted in the urine. Paclitaxel's clearance is decreased by almost 25 to 33% when paclitaxel is administered after cisplatin.
Paclitaxel is minimally removed by hemodialysis.
43.4 mL: 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. Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 L/hr/m²; total body clearance appeared to decrease with higher plasma concentrations of Paclitaxel. Mean steady-state volume of distribution ranged from 198 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m² to 175 mg/m², the C_max and AUC → ∞values increased 75% and 81%, respectively.
Following an intravenous dose of 100 mg/m² given as a 3-hour infusion to 19 KS patients, the mean C_max 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).
Intrapatient variability in systemic Paclitaxel exposure was minimal. There was no evidence for accumulation of Paclitaxel with multiple treatment courses.
In vitro studies of binding to human serum proteins indicate that 89-98% of medicinal product is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of Paclitaxel.
The disposition of Paclitaxel has not been fully elucidated in humans. Mean values for cumulative urinary recovery of unchanged drug have ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of Paclitaxel. Paclitaxel appears to be metabolized primarily by cytochrome P450 enzymes. Following administration of a radiolabelled paclitaxel, an average of 26, 2 and 6% of the radioactivity was excreted in the feces as 6a-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel, and 6a-3'-p-dihydroxy-paclitaxel, respectively. The formation of these hydroxylated metabolites is catalyzed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 respectively. The effect of renal or hepatic dysfunction on the disposition of Paclitaxel following a 3-hour infusion has not been investigated formally. Pharmacokinetic parameters obtained from one patient undergoing hemodialysis who received a 3-hour infusion of Paclitaxel 135 mg/m² were within the range of those defined in non-dialysis patients.
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 medicinal product.