Avoxred Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacitidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA. DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer-suppressing functions to cancer cells. The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.
Pharmacokinetics: Absorption: Following subcutaneous administration of a single 75 mg/m² dose, azacitidine was rapidly absorbed with peak plasma concentrations of 750 ± 403 ng/mL occurring at 0.5 h after dosing (the first sampling point). The absolute bioavailability of azacitidine after subcutaneous relative to intravenous administration (single 75 mg/m² doses) was approximately 89% based on area under the curve (AUC).
Area under the curve and maximum plasma concentration (C_max) of subcutaneous administration of azacitidine were approximately proportional within the 25 to 100 mg/m² dose range.
Distribution: Following intravenous administration, the mean volume of distribution was 76 ± 26 L, and systemic clearance was 147 ± 47 L/h.
Biotransformation: Azacitidine metabolism does not mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs).
Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. In human liver S9 fractions, formation of metabolites was independent of NADPH implying that azacitidine metabolism was not mediated by cytochrome P450 isoenzymes. Azacitidine does not induce CYP 1A2, 2C19, or 3A4 or 3A5. Inhibition of a series of P450 isoenzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) azacitidine up to 100 μM did not produce inhibition. Therefore, CYP enzyme induction or inhibition by azacitidine at clinically achievable plasma concentrations is unlikely.
Elimination: Azacitidine is cleared rapidly from plasma with a mean elimination half-life t_1/2 after subcutaneous administration of 41 ± 8 minutes. No accumulation occurs after subcutaneous administration of 75 mg/m² azacitidine once daily for 7 days. Urinary excretion is the primary route of elimination of azacitidine and/or its metabolites. Following intravenous and subcutaneous administration of ¹⁴C-azacitidine, 85 and 50 % of the administered radioactivity was recovered in urine respectively, while < 1 % was recovered in faeces.
Special populations: The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been formally studied.
Renal impairment: Azacitidine can be administered to patients with renal impairment without initial dose adjustment provided these patients are monitored for toxicity since azacitidine and/or its metabolites are primarily excreted by the kidney.
Pharmacogenomics: The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not been formally investigated.