Abstract 2321: SGI-110 SQ provides superior disposition profile for active metabolite decitabine than decitabine IV infusion: Results from mass balance and tissue distribution study in cynomolgus monkeys and in vitro human studies
Authors: Oganesian Aram , McClanahan Robert H. , Solon Eric , Azab Mohammad 
Published: May 2015

Introduction: SGI-110 is 2nd generation hypomethylating agent (HMA) formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume and pharmaceutically stable subcutaneous (SQ) injection allowing longer effective half-life and more extended DAC exposure window than IV infusion. As previously reported, the differentiated PK profile offers the potential for improved biological and clinical activity and safety over currently available HMAs (Kantarjian et al. ASH, 2012).

Objective: The aim of this study was to characterize the mass balance and tissue distribution of [14C]SGI-110 compared to IV DAC and evaluate the potential uptake into cells of SGI-110 in parent form prior to conversion to active metabolite DAC.

Methods: The mass balance (MB) of administered radioactivity was evaluated in cynomolgus monkeys following a single SQ dose of [14C]SGI-110 or a single molar equivalent IV infusion dose of [14C]decitabine. Tissue distribution of the radiolabel was determined using quantitative whole-body autoradiography (QWBA) up to 24 hours following dosing. The position of the radiolabel was within the DAC structure of SGI-110 and the same as on DAC. SGI-110 was evaluated as a substrate in human transporter panel and its uptake into cells was also assessed by incubation with fresh human whole blood.

Results: Excretion of radioactivity after SGI-110 SQ dosing was predominantly urinary while only 3% of the dose was detected in feces. Recovery of the radioactive dose was complete over 24 hr. For bone marrow, blood, plasma, red blood cells (RBC), white blood cells and most tissues examined, total radioactivity-derived concentrations following SGI-110 dosing were consistently higher than for IV DAC (based on molar equivalency comparison), suggesting that higher levels of DAC-related exposures are achieved at potential target sites with SGI-110. SGI-110 was detected at appreciable levels in RBC lysates from monkey MB study suggesting intracellular presence, which was then confirmed in incubation with fresh human whole blood where intracellular SGI-110 was detected in RBC and WBC lysates. In vitro transporter panel study showed SGI-110 to be a substrate for uptake by human CNT2-expressing MDCK-II cells, while decitabine was a substrate for human nucleoside transporters CNT1 and ENT1.

Conclusions: Results show that SQ SGI-110 delivers consistently higher decitabine-related exposures at target tissues confirming its potential for improved clinical activity over DAC IV infusion. This is likely the result of the enhanced disposition profile conferred by protracted SGI-110 conversion affording a more extended exposure window of active metabolite decitabine and the intracellular uptake of SGI-110 for overall increased exposure at target sites of action.

Citation Format: Aram Oganesian, Robert H. McClanahan, Eric Solon, Mohammad Azab. SGI-110 SQ provides superior disposition profile for active metabolite decitabine than decitabine IV infusion: Results from mass balance and tissue distribution study in cynomolgus monkeys and in vitro human studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2321. doi:10.1158/1538-7445.AM2014-2321