Paxoll Mechanism of Action

Pharmacology: Paclitaxel is a novel 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.
Following intravenous administration of PAXOLL, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
Pharmacokinetic parameters of paclitaxel following 3-and 24-hour infusions of PAXOLL at dose levels of 135 and 175 mg/m² are determined in a Phase 3 randomized study in ovarian cancer patients. It appeared that with the 24-hour infusion of PAXOLL, a 30% increase in dose (135 mg/m² versus 175 mg/m²) increased the C_max by 87%, whereas the AUC_(0-∞) remained proportional. However, with a 3-hour infusion for a 30% increase in dose, the C_max and AUC_(0-∞) are increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state with the 24-hour infusion of PAXOLL ranged from 227 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel are also evaluated in adult cancer patients who received single doses of 15-135 mg/m² given by 1-hour infusions (n=15), 30-275 mg/m² given by 6-hour infusions (n=36), and 200-275 mg/m² given by 24-hour infusions (n=54) in Phase 1 and 2 studies.