Azacitidine - How It Works
Clinical pharmacology details from the US FDA-approved label: how Azacitidine works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action VIDAZA is a pyrimidine nucleoside analog of cytidine. VIDAZA is believed to exert its antineoplastic effects by causing hypomethylation of DNA 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.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action VIDAZA is a pyrimidine nucleoside analog of cytidine.
VIDAZA is believed to exert its antineoplastic effects by causing hypomethylation of DNA 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.
12.2 Pharmacodynamics In pediatric patients with JMML post azacitidine treatment (75 mg/m 2 or 2.5 mg/kg), reductions in genome-wide DNA methylation (global DNA methylation scores) were attained in bone marrow granulocytes during the first treatment cycle, confirming the DNA-hypomethylating activity of azacitidine.
12.3 Pharmacokinetics The pharmacokinetics of azacitidine were studied in 6 adult patients with MDS following a single 75 mg/m 2 subcutaneous dose and a single 75 mg/m 2 intravenous dose.
Absorption Azacitidine is rapidly absorbed after subcutaneous administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour after subcutaneous administration.
Distribution The bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on area under the curve.
Mean volume of distribution following intravenous dosing is 76 ± 26 L.
Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration is 41 ± 8 minutes.
The AUC and C max of subcutaneous administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m 2 dose range.
Multiple dosing at the recommended dose-regimen does not result in drug accumulation with intravenous or subcutaneous administration.
Elimination Metabolism An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine is not metabolized by the cytochrome P450 (CYP) enzymes.
Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase.
Excretion Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites.
Following intravenous 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.
Mean excretion of radioactivity in urine following subcutaneous administration of 14 C-azacitidine was 50%.
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetics of azacitidine were studied in 6 adult patients with MDS following a single 75 mg/m 2 subcutaneous dose and a single 75 mg/m 2 intravenous dose. Absorption Azacitidine is rapidly absorbed after subcutaneous administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour after subcutaneous administration. Distribution The bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following intravenous dosing is 76 ± 26 L. Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration is 41 ± 8 minutes. The AUC and C max of subcutaneous administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m 2 dose range. Multiple dosing at the recommended dose-regimen does not result in drug accumulation with intravenous or subcutaneous administration. Elimination Metabolism An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine is not metabolized by the cytochrome P450 (CYP) enzymes. Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Excretion Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following intravenous administration of radioactive azacitidine t