Methods

Relative circulating levels of astaxanthin derived from CDX-085 administration compared to administration of pure astaxanthin was initially evaluated in a canine model. In mouse Study #1, 16 wild-type and 16 LDLR^{鈭?鈭?/sup> mice on 0.5%cholesterol diet supplemented with either 0.0%, 0.08%, 0.2%and 0.4%CDX-085 were used to assess plasma levels and lipoprotein biodistribution measured by FPLC after 4 weeks treatment. In Study #2, 36 male LDLR鈭?鈭?/sup> mice were randomized to a 0.5%cholesterol chow diet (CHOW group, n = 12) or 0.5%cholesterol chow fortified with 0.08%CDX-085 (n = 12) or 0.5%cholesterol chow with 0.4%CDX-085 (n = 12) for 12 weeks. In Study #3, 34 male ApoE鈭?鈭?/sup> mice were randomized in the same fashion as the Study #2 and fed similar diets for 9 weeks.}

Results

CDX-085 administration was shown to result in significantly higher levels of circulating astaxanthin (p < 0.001 ANOVA) over a 72 h period compared to pure, non-esterified astaxanthin in a single-dose pharmacokinetic study in beagles. In Study #1, plasma astaxanthin levels were 5-9-fold higher in LDLR^{鈭?鈭?/sup> mice compared to wild-type mice. Astaxanthin was highly distributed among all lipoprotein fractions, generally reflecting cholesterol content of lipoproteins. In Study #2, administration of CDX-085 resulted in significantly lower total cholesterol levels (528 卤 68 mg/dL vs. 550 卤 67 mg/dL vs. 602 卤 80 mg/dL, p = 0.047) and aortic arch atherosclerosis (9.0 卤 4.2%vs. 9.8 卤 3.5%vs. 13.2 卤 3.6%, p = 0.023) in the 0.4%CDX-085 group compared to the 0.08%CDX-085 and CHOW groups, respectively. In ApoE鈭?鈭?/sup> mice, a 72%reduction in triglycerides in the 0.4%CDX-085 group and 50%reduction in the 0.08%CDX-085 groups was noted compared to CHOW group (final levels 17 卤 11 mg/dL vs. 30 卤 15 mg/dL vs. 60 卤 32 mg/dL, respectively, p = 0.001).}

Conclusion

Oral administration of the novel astaxanthin prodrug CDX-085 shows that it distributes among lipoproteins. CDX-085 lowers total cholesterol and aortic arch atherosclerosis in LDLR^{鈭?鈭?/sup> mice and triglyceride levels in ApoE鈭?鈭?/sup> mice and shows promise for further evaluation in human studies.}