Azacord Mechanism of Action

Antineoplastic.
Pharmacology: Pharmacodynamics: Mechanism of action: Azacitidine is a pyrimidine nucleoside analog of cytidine, believed to exert its antineoplastic effects by DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.
Clinical Studies: As a form of relatively low-intensity chemotherapy, the DNA methyltransferase inhibitor (DMTI) hypomethylating agent 5-azacytidine has been shown in randomized phase III trials to improve overall survival and quality of life and to decrease the risk of leukemic transformation. Hematologic responses occurred in 60% of patients in the azacitidine arm (10-17% complete response, 16% partial response, 23-36% hematological improvement) compared with an overall 5% response rate (only hematologic improvements) in those receiving supportive care. Additionally, the time to progression to AML or death was improved in those who received azacitidine earlier in the course of disease, suggesting that the drug prolonged the duration of stable disease. Median number of cycles to first response was 3. Data from a randomized trial for higher-risk MDS concluded that azacitidine was superior to conventional care (standard chemotherapy or supportive care) in overall survival. Azacitidine treatment was associated with a median survival of 24.46 months versus 15.02 months for those receiving conventional care, a difference of 9.4 months (p= 0.0001). The hazard ratio for the treatment effect was 0.58 (95% CI: 0.43-0.77) with two-year survival rates of 50.8% with azacitidine compared to 26.2% with conventional care (p <0.0001). The survival benefits of azacitidine were consistent regardless of the conventional care option, cytogenetic subgroups, or age. Azacitidine treatment was associated with a median time to death or transformation to AML of 13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 months (p= 0.0025). Azacitidine treatment was also associated with a reduction in cytopenias, and their related symptoms; higher proportion of transfusion independency for longer duration.
Pharmacokinetics: The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m² subcutaneous (SC) dose and a single 75 mg/m² intravenous (IV) dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour with relative bioavailability of approximately 89% for SC azacitidine. Mean volume of distribution following IV dosing is 76 ± 26 L with mean SC clearance is 167 ± 49 L/hour and mean half-life after SC administration is 41 ± 8 minutes. Published studies indicate that urinary excretion is the primary route of elimination ofazacitidine and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over 3 days.