A. Oganesian,1 O. Demin, Jr.,2 A. Nikitich,2 O. Demin,2 M. Azab1; 1Astex Pharmaceuticals, Dublin, CA, 2Institute for Systems Biology, Moscow, Russian Federation
BACKGROUND: Treatment for acute myeloid leukemia (AML) targets reduction of abnormal cell proliferation rate. Decitabine (DAC), a well characterized hypomethylating agent (HMA), is incorporated into DNA during the S-phase; inhibits methylation; helps re-expression of tumor suppressor genes; and induces G2/M arrest. SGI-110, a second generation HMA given subcutaneously (SQ), was designed to increase in vivo exposure of its active metabolite DAC. This work explored how changes in exposure window of DAC affect DNA demethylation and tumor cell proliferation in AML patients.
METHODS: A systems pharmacology model was developed to characterize myeloblasts transition between cell cycle phases and proliferation of healthy neutrophils; PK of DAC after IV infusion or SQ SGI-110; LINE-1 demethylation; and progression of AML. Model parameters were calculated using literature data or fitted against experimental data.
RESULTS: The model satisfactorily reproduced in vitro data with myeloblasts cell lines showing proliferation and distribution between cell cycle in the presence or absence of DAC; LINE-1 demethylation after IV DAC and SQ SGI-110; blast levels in blood during AML progression of patients with and without treatment by HMAs. The model shows that administration of SGI-110 SQ at 60 mg/m2 (Days 1-5 of a 28-day cycle) induces LINE-1 demethylation at a higher level compared to IV DAC due to wider exposure window of the active metabolite. In simulation of 6 treatment cycles in low and highly proliferative virtual AML patients, longer DAC exposure window results in a more pronounced effect on myeloblast proliferation in bone marrow and reduction of blasts in peripheral blood.
CONCLUSION: Increased exposure window of decitabine post treatment with SGI-110 SQ may result in higher efficacy in treatment of AML.