Nanoxel Mechanism of Action

Pharmacology: Mechanism of Action: Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of 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: Pharmacokinetic parameters of paclitaxel nanoparticle injection were evaluated in 29 patients after the 1st cycle and 23 patients after the 2nd cycle during the 1st two courses of therapy to account for intra-patients variations if any. The studied doses ranged from 135-375 mg/m². No significant difference was noted in AUC and C_max values between the 2 cycles, thus indicating absence of cumulative effect.
It was observed that pharmacokinetic parameters best fitted into a 2-compartment model. Pharmacokinetic analysis has shown a linear correlation between the mean AUC and dose up to 375 mg/m². Paclitaxel pharmacokinetics per se follows 2 compartmental model and paclitaxel nanoparticle injection does not alter the basis pharmacokinetic characteristics of paclitaxel. The drug exposure (AUCs) was dose proportional over 135-375 mg/m². At 200 and 300 mg/m² dose level of paclitaxel nanoparticle injection, the mean maximum concentration of paclitaxel (C_max) at the end of infusion, was 5859.36 ng/mL and 11682.72 ng/mL, respectively.
The mean total clearance at 200 mg/m² dose level was 32.4 L/hr and the volume of disturbance was 76.8 L. No significant interindividual variation was observed in PK profile of the formulation. PK behavior was consistent showing that reconstitution did not introduce any significant variability.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1-50 mcg/mL, indicate that between 89-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of paclitaxel.
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to 2 minor metabolites, 3'-p-hydroxypaclitaxel and 6a, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers or inhibitors of CYP2C8 and/or CYP3A4.
The effect of renal or hepatic dysfunction on the disposition of paclitaxel nanoparticle injection has not been investigated. Clinical Studies: The safety and efficacy of paclitaxel nanoparticle injection was evaluated as monotherapy in patients with metastatic breast cancer who relapsed on 1st line therapy with anthracyclines or locally advanced or recurrent breast cancer that relapsed after adjuvant therapy with anthracyclines, in an open label, randomized, multicenter study.
Patients were randomized to receive either paclitaxel nanoparticle injection or conventional paclitaxel. Paclitaxel nanoparticle injection infusion was given over a period of 1-hr every 3 weeks at two different doses of 300 mg/m² (Arm B) and 220 mg/m² (Arm C). Conventional paclitaxel was administered to patients in Arm A at the therapeutically approved dose of 175 mg/m² (3-hr infusion, every 3 weeks).
At the time of interim report submission, out of 193 patients, 168 were analyzed for efficacy. Objective response (OR) was observed in 38.2% of patients receiving paclitaxel nanoparticle injection at 220 mg/m² dose as compared with 32.3% in patients receiving conventional paclitaxel. There were more percentage of patients who progressed while on therapy with conventional paclitaxel as compared to those on paclitaxel nanoparticle injection 220 mg/m² (35.5% vs 27.3% respectively).
A higher clinical benefit (CR+PR+SD) was observed with paclitaxel nanoparticle injections 220 mg/m² (85.4%) as compared to conventional paclitaxel (74.2%).