Paclitaxel Formulations GenexolPM and NK105

Similar to doxorubicin, there are two promising formulations of paclitaxel that are under clinical trial evaluation: Genexol-PM and NK105. The main pharmacokinetic parameters of paclitaxel administered as Genexol-PM at a dose of 135 mg/m2 are 5473 ng h/mL for the AUC and 12.7 h for the t1/2p; whereas for paclitaxel administered as Taxol®, the AUC is 9307.5 ng h/mL, and the t1/2 = 20.1 h.90,149 In this way, the Genexol-PM formulation does not improve the pharmacokinetic profile of paclitaxel in vivo; therefore, the micelles in this formulation function primarily as solubilizers. In fact, it has been found that the drug is released quite rapidly from the PEG-b-PDLLA micelles following administration. However, as a result of the low toxicity of the micelles in comparison to Cremophor EL (the primary excipient in Taxol®), the advantage of this formulation is the significant improvement in the maximum tolerated dose (i.e., MTD = 390 mg/m2) when compared to the MTD of paclitaxel administered as Taxol® (i.e., 135-200 mg/m2).90,149 In this case, the increase in the MTD is attributed to the biocompatibility or non-toxicity of the

PEG-b-PDLLA copolymers. Therefore, an improvement in the anti-cancer efficacy may be expected because of the higher dose of paclitaxel that may be administered when given as the Genexol-PM formulation.

NK105 is a micelle formulation of paclitaxel wherein the micelles have been shown to perform as true carriers. The NK105 micelles are formed from copolymers with PEG as the hydrophilic block and modified PAsp as the core-forming block. The PAsp block is conjugated with 4-phenyl-1-butanol as a means to increase the compatibility between the micelle core and paclitaxel. Paclitaxel administered in the NK105 formulation has been shown to have a much longer circulation lifetime than paclitaxel administered as Taxol®. Specifically, the AUC for paclitaxel was increased by 50-86-fold and the t1/2 was increased 4-6 times for the NK105 formulation in comparison to paclitaxel administered as Taxol®.99 In addition, the therapeutic efficacy of NK105 and Taxol® formulations were investigated in an HT-29 colon cancer xenograft model in nude mice. The NK105 formulation was found to exhibit statistically superior anti-tumor activity in comparison to Taxol®. The anti-tumor activity of NK105 administered at a paclitaxel-equivalent dose of 25 mg/ kg was comparable to that obtained following the administration of Taxol® at a paclitaxel dose of 100 mg/kg. In addition, all tumors disappeared in the NK105 treatment group following one dose of 100 mg/kg, and all mice remained tumor-free for the 33-day duration of the study. This significant improvement in the anti-cancer activity of paclitaxel following encapsulation in this micelle system may be attributed to the ability of the NK105 micelles to function as true drug carriers.

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