Background: Docetaxel (Taxotere) is currently formulated in the surfactant Tween 80. Removal of surfactants from taxane formulations e.g., in the case of nanoparticle albumin-bound paclitaxel (Abraxane) resulted in significantly higher response rates and greater safety (Gradishar, JCO, 2005, 23:7794). Tween 80 strongly inhibited the binding of taxanes to albumin, possibly inhibiting albumin based drug transport via the gp60 endothelial receptor (Desai, EORTC-NCI-AACR, 2004) and consequent reduction of albumin-binding to tumor secreted SPARC. Herein, we compared the efficacy, toxicity, and pharmacokinetics (PK) of nab-docetaxel vs Taxotere. Methods: Nanoparticle nab-docetaxel was prepared using nab technology and characterized. Nab-docetaxel and Taxotere were tested in vivo against HCT-116 human colon carcinoma xenograft in nude mice (n=10/group) at equitoxic doses of 22 mg/kg of nab-docetaxel and 15 mg/kg of Taxotere, on a q4dx3 schedule. Single dose toxicity (TOX) of nab-docetaxel was compared to Taxotere in rats at 25, 50, 75, 100, and 125 mg/kg (N=3 per group). Multiple dose TOX of nab-docetaxel was compared to Taxotere in rats at 5, 10, 15, 30, and 50 mg/kg on a q4dx3 schedule (N=3 per group). PK of nab-docetaxel and Taxotere were evaluated in rats at 10, 20, and 30 mg/kg (N=3 per group). Results: In vivo, both nab-docetaxel and Taxotere were effective against HCT-116. However, at equitoxic dose, as measured by weight loss, nab-docetaxel exhibited significantly higher antitumor activity versus Taxotere (p<0.0001, ANOVA). In the single dose TOX study, mortality was more rapid and complete for Taxotere at all dose levels in comparison to nab-docetaxel. The LD50 was calculated to be 63 mg/kg for nab-docetaxel versus approximately 12.5 mg/kg for Taxotere. In the multiple dose TOX study, mortality was similar for nab-docetaxel and Taxotere, with complete survival only at the lowest dose level of 5 mg/kg. At this dose level, weight loss, neutropenia, and organ toxicity were significantly less for nab-docetaxel versus Taxotere. The PK at 10 mg/kg for nab-docetaxel and Taxotere was similar. However, the differences were significant at both 20 mg/kg and 30 mg/kg dose levels with Cmax and AUC lower and Vz and Vss higher for nab-docetaxel versus Taxotere. The AUC vs dose relationship was linear for nab-docetaxel and exponential for Taxotere. Conclusion: Nab-docetaxel was significantly less toxic than Taxotere. At equitoxic dose, nab-docetaxel showed significantly improved antitumor activity against HCT-116 colon tumor and equivalent safety despite 50% higher dose. The PK results suggest tween-sequestration of docetaxel in plasma for Taxotere, These observations are similar to those previously seen for nab-paclitaxel (Abraxane) vs Taxol.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]