Abstract 1297: DDAIP improves the pharmacokinetic profile of PrevOnco® in different species: Comparison of DDAIP, CMC and PEG-300/400 formulations in mice, beagle dogs and cynomolgus monkeys

Our study in the accompanying abstract demonstrates that a low dose of PrevOnco® in combination with doxorubicin was efficacious in a liver cancer model. In this study we investigated the pharmacokinetic profile of PrevOnco® when formulated with 20% DDAIP or 20% PEG-300 in mice, dogs and cynomolgus monkeys. The goal was to evaluate the potential of formulation in DDAIP to increase PrevOnco® exposure in vivo. Methods: PK plasma analyses of PrevOnco® administered orally at 100 mg/Kg in 1% carboxy methyl cellulose (CMC) or in 10% PEG-400 were evaluated in nude mice. 20% PEG-300 and 20% DDAIP formulations were evaluated in mice (100 mg/Kg), dogs (5 mg/Kg) and monkeys (5 mg/Kg). Results: Compared to 20% PEG-300, administration of PrevOnco® in 20% DDAIP induced 7-fold, 8-fold and 2-fold improvements in AUC in mice, dogs and cynomolgus monkeys, respectively. In mice, C max reached 4,700 ng/mL in DDAIP compared to 1,000 ng/mL in PEG-300 formulation. PrevOnco® levels were detectable up to 4 hours in DDAIP compared to 2 hrs in PEG-300. In dogs, PrevOnco® in 20% PEG-300 formulation had a C max of 125 ng/mL at T max = 1 hr. This concentration was maintained up to 2 hrs with levels undetectable at 4 hrs. PrevOnco® in 20% DDAIP formulation had a C max of 1,600 ng/mL at T max =1 hr and T 1/2 =3hrs. AUC values were 3,941 and 477 for DDAIP and PEG, respectively. In monkeys, PrevOnco® plasma levels following 5 mg/Kg oral administration reached a C max of 120 ng/mL in 20% DDAIP and 90 ng/mL in 20% PEG-400. T max was 1 hour and 0.5 hour while AUCs were 390 versus 154 (both DDAIP vs. PEG-400). Conclusion: Formulating with DDAIP increased plasma levels of PrevOnco® following oral administration in mice, dogs and monkeys. Thus, DDAIP facilitated higher C max and AUC values as well as a longer T 1/2 . DDAIP formulation will allow a lower dose of PrevOnco® to be used while maintaining efficacy and reducing cytotoxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2011-1297