Paxus PM Mechanism of Action

Pharmacology: Pharmacodynamics: PAXUS PM for injection is polymeric micelle formulation of Paclitaxel. Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimmers 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 additional, Paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Pharmacokinetics: The pharmacokinetics of total Paclitaxel following infusion of PAXUS PM over 3 hours at doses of 135, 175, 230, 300 and 390 mg/m² were determined in clinical study. The pharmacokinetic parameters of Paclitaxel from PAXUS PM studies demonstrated a low degree of variability and increased dose proportionally over the dose range tested.
The mean Paclitaxel concentration-time profiles following an infusion of PAXUS PM were characterized by a pronounced distribution phase followed by the terminal elimination phase. Within 5 to 15 minutes of the end of the infusion, Paclitaxel concentrations dropped to one-half or one-third of the peak level. With the constant­-rate infusion of PAXUS PM, maximum plasma Paclitaxel concentrations were observed between 1.45 and 3.22 hours after the start of the infusion. Mean values of Cmax of Paclitaxel ranged from 714 ng/mL (at the dose of 85 mg/mm²) to 6,567 ng/mL (at the dose of 390 mg/m² in PAXUS PM infusion).
At the recommended clinical dose of PAXUS PM, 300 mg/m², the mean maximum concentration of Paclitaxel was 3,107 ng/mL, which is a little lower than the value reported for the patients received 3-hour infusion of Paclitaxel 175 mg/m². Mean values of the Paclitaxel half-life after the administration of PAXUS PM ranged from 11.0 to 17.9 hours which were consistent with the values reported in the product label for Paclitaxel (13.1 hours for 135 mg/m² and 20.2 hours for 175 mg/mm²).
Mean values of the total area under the curve (AUC_inf) ranged from 2,790 to 27,491 ng-hr/mL in the dose range tested. Considering the mean AUC values, greater systemic exposures were inferred after Paclitaxel infusion than after comparable dosing regimens of PAXUS PM. At 175 mg/m² dose levels, the AUC values obtained after Paclitaxel infusion were 2.6 times greater than that obtained after PAXUS PM infusion. The mean values of total systemic clearance of Paclitaxel following 3-hour infusions of PAXUS PM were 12.1-33.3 l/hr/m. The mean V_d of Paclitaxel in the terminal elimination phase following PAXUS PM infusion ranged from 328 to 897 l/m², which is significantly greater than the V_d of Paclitaxel estimated in Paclitaxel infusion (67 to 182 l/m²: calculated from the mean values of CL and T_½ reported), suggesting that the PAXUS PM formulation produces greater distribution to the periphery compared to Paclitaxel.
No drug interaction studies have been conducted with PAXUS PM. However, it is known that the metabolism of Paclitaxel is catalyzed by CYP2C8 and CYP3A4. Thus, caution should be exercised when administering PAXUS PM concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4. Potential interactions between Paclitaxel, a substrate of CYP3A4 and protease inhibitors (such as Ritonavir, Saquinavir, lndinavir, and Nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.