Abstract Background: SGI-110 is a second generation hypomethylating agent consisting of a dinucleotide of decitabine and deoxyguanosine designed to release decitabine upon administration. SGI-110 is being evaluated in patients with relapsed/refractory MDS and AML. This study evaluated pharmacodynamic effects of three alternate weekly intermittent dosing schedules of Subcutaneous (SQ) SGI-110, and also the bioavailability of SGI-110 when given orally. Methods: Group A received a single 10 mg/kg dose of SGI-110 by oral gavage. Group B received SQ injections of 1.5 mg/kg on Days 1,2, 8,9 and 15,16; Group C received SQ injections on Days 1,4, 8,11, 15 and 18; group D received injections on Days 1,2,3 and 15,16,17. Pharmacokinetics of SGI-110 and decitabine were evaluated on Day 1 for all treatment groups. The pharmacodynamic effect of SGI-110 was assessed through Day 28 (Days 1, 4, 8, 11, 14, 21 and 28) by measuring LINE1 methylation status in PBMCs from monkeys in groups B, C and D. Results: Animals tolerated SGI-110 treatment well through the study. Relative oral bioavailability of decitabine appeared to be very low with only trace amounts of decitabine detected in plasma from Group A animals. A time-dependent LINE1 hypomethylating effect was observed in monkeys from Groups B, C and D relative to baseline pre-treatment values from Day 1. The maximal extent of hypomethylation varied between 11-14% within the groups and was achieved earlier in the cycle for Groups B and C (Day 11 and Day 14, respectively), whereas for Group D a second maximum peak effect was observed on Day 21. All groups trended towards baseline by Day 28 but Groups C and D still had significant hypomethylation (8-9%) present by the end of the study. On average, Group C and D seemed to achieve the maximum and most prolonged hypomethylation but only group C had a sustained effect. Conclusions: SGI-110 was well tolerated in cynomolgus monkeys for both single PO and repeat SQ dosing using intermittent alternate-weekly schedules. Oral bioavailability of SGI-110 was very low, suggesting very high first-pass contribution to SGI-110 and decitabine clearance upon oral administration. All SQ schedules achieved significant hypomethylating effect; the extent and the duration of effect were more favorable for Groups C and D with group C showing a more sustained effect over the 28-day cycle. We concluded that the twice weekly SQ regimen is a highly effective and convenient regimen to study in clinical trials as it may achieve a more sustained pharmacodynamic effect. Citation Format: Aram Oganesian, Pietro Taverna, Mohammad Azab. Evaluation of oral bioavailability and intermittent dosing schedules for pharmacodynamic effects by SGI-110, a novel subcutaneous (SQ) second generation hypomethylating agent (HMA), in male cynomolgus monkeys . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 678. doi:10.1158/1538-7445.AM2013-678