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Background: Docetaxel is a semi-synthetic taxane analog commonly used in the treatment of non-small cell lung, prostate, and breast cancer. Docetaxel is poorly water-soluble and must be formulated with co-solvents that can potentially contribute to treatment-related adverse events such as hypersensitivity reactions. Azaya Therapeutics, Inc. has developed a novel propriety nanotechnology-based platform called Protein Stabilized Liposomes (PSLTM) that avoids these major formulation issues, producing a safer and more efficacious targeted drug delivery system. Pharmacokinetic (PK) and tumor growth inhibition studies were conducted in murine xenograft models using Azaya’s PSL formulated docetaxel (ATI-1123) preparation.

Methods: Female Sprague-Dawley rats were dosed with 5, 10, or 20 mg/kg of standard docetaxel (13% ethanol, 25% Tween 80 (v/v), 62% saline (0.9%) vehicle) or ATI-1123 (sterile water vehicle). Plasma samples for PK analysis were obtained at 11 time points ranging from time zero to 72 hrs. Total plasma docetaxel concentrations were analyzed by LC-MS/MS and PK parameters were calculated by non-compartmental methods using WinNonlin 4.1.

Results: Plasma elimination of docetaxel following ATI-1123 and standard docetaxel was initially rapid, followed by a slower elimination rate out to 72 hours. Overall, the docetaxel AUC values for ATI-1123 were 4-fold or greater than the AUC observed following treatment with standard docetaxel for all doses. At 20 mg/kg, the ATI-1123 docetaxel AUC was 8.13 mg-h/mL versus 1.27 mg-h/mL for standard docetaxel. The Cmax values were 3-fold or higher for the ATI-1123 formulation versus the standard formulation over all 3 dose levels. As the dose level increased from 5 to 20 mg/kg, both AUC and Cmax increased dose proportionally. Overall, these differences in systemic exposure corresponded to a 4 to 5-fold faster clearance of standard docetaxel compared to the ATI-1123 liposomal formulation, independent of the dose level tested.

Conclusions: Total systemic docetaxel exposures were substantially enhanced following PSL-formulated ATI-1123 docetaxeladministration compared to standard docetaxel. Differences between the two formulations were consistent across the 5, 10, and 20 mg/kg doses explored in the study. These data strongly support further investigation of ATI-1123 to analyze alterations in drug distribution, tolerability, and anti-tumor efficacy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA