Doxorubicin Formulations SP1049C and NK911

SP1049C includes doxorubicin formulated in L61 and F127 Pluronic® copolymers at a ratio of 1:8 (wt/wt).26 For doxorubicin administered in the SP1049C formulation at a dose of 10 mg/kg, the AUC in healthy mice was found to be 14.6 mg h/mL while the maximum concentration (Cmax) in plasma was 4.47 mg/g. For doxorubicin administered as free drug, the AUC is 7.1 mg h/mL and the Cmax in plasma is 2.77 mg/g. In this way, the SP1049C formulation provides a 2.1-fold increase in the AUC.

NK911 is another micelle formulation of doxorubicin and includes both chemically and physically entrapped doxorubicin within PEG-b-PAsp micelles. In its phase I trial, the administration of the NK911 formulation at a dose of 50 mg/m2 was shown to provide a significant increase in the half-life (t1/2) and the AUC as well as a significant decrease in the steady state volume of distribution (Vss). Specifically, for doxorubicin administered to humans in NK911, the t1/2 values were reported to be t1/2,a = 7.5 min, i1/2,p = 2.8 h, and i1/2,g = 64.2 h, and the AUC was found to be 3262.7 ng h/mL, and the Vss was 14.9 L/kg. In comparison to free doxorubicin, the t1/2 values were reported to be t1/2,a = 2.4 min, i1/2,p = 0.8 h, and i1/2,g = 25.8 h, and the AUC was found to be 1620.3 ng h/mL, and the Vss was 24 L/kg.82 In this way, the encapsulation of doxorubicin in the NK911 formulation increases the AUC and plasma Cmax for this drug by 36.4 and 28.6-fold, respectively. The change in the pharmacokinetic profile of the drug translates into changes in the efficacy and toxicity of the encapsulated agent. Specifically, the anti-tumor activity was evaluated in four tumor xenograft models in mice, namely, Colon 26, M5076, P388, and Lu-24. For the groups of animals receiving treatment with the micelle-formulated drug, a significant percentage of mice bearing colon 26 and MX-1 tumors were cured, whereas no cures were found for mice who received the same dose of free doxorubicin. Moreover, in all tumor models, treatment with the free drug resulted in more severe toxicity than that observed in animals receiving even the highest dose of NK911.

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