Source: Australian Department of Health
Decitabine is a nucleoside metabolic inhibitor that is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into deoxyribonucleic acid (DNA) and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation, proliferation, and the immune system. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. At the recommended Inqovi 35/100 dose, maximal or near maximal pharmacodynamic effect of long interspersed nucleotide elements-1 (LINE-1) demethylation was observed over the range of decitabine systemic exposures based on modelling.
Cedazuridine inhibits cytidine deaminase (CDA). CDA is an enzyme that is responsible for the degradation of nucleosides, including decitabine. High levels of CDA in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability. Oral administration of cedazuridine with decitabine enhances the oral bioavailability of decitabine via inhibition of first pass metabolism of decitabine in the gut and liver by CDA.