ansferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs).
Metabolism of azacitidine is by spontaneous hydrolysis and by deamination mediated by cytidine deaminase. In human liver S9 fractions, formation of metabolites was independent of NADPH implying any metabolism would be catalysed by cytosolic enzymes. An in vitro study of azacitidine with cultured human hepatocytes indicates that at concentrations of 1.0 µM to 100 µM (i.e. up to approximately 30-fold higher than clinically achievable concentrations), azacitidine does not induce cytochrome P450 isoenzymes (CYP) 1A2, 2C19, or 3A4 or 3A5. In studies to assess inhibition of a series of P450 isoenzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) incubated with 100 µM azacitidine, IC50 values could not be determined, therefore, enzyme inhibition by azacitidine at clinically achievable plasma concentrations is unlikely.
Excretion
Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t½) 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 renal or hepatic impairment (see section 4.2), gender, age, or race on the pharmacokinetics of azacitidine have not been formally studied.
Pharmacogenomics
The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not been formally investigated.
5.3 Preclinical safety data
Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammalian cell systems in vitro. The potential carcinogenicity of azacitidine was eva luated in mice and rats. Azacitidine induced tumours of the haematopoietic system in female mice, when administered intraperitoneally 3 times per week for 52 weeks. An increased incidence of tumours in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine administered intraperitoneally for 50 weeks. A tumorigenicity study in rats revealed an increased incidence of testicular tumours.
Early embryotoxicity studies in mice revealed a 44 % frequency of intrauterine embryonal death (increased resorption) after a single intraperitoneal injection of azacitidine during organogenesis. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before closure of the hard palate. In rats, azacitidine caused no adverse effects when given pre-implantation, but it was clearly embryotoxic during when given during organogenesis. Foetal abnormalities caused during organogenesis included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly) and others (micrognathia, gastroschisis, oedema, and rib abnormalities).
Administration of azacitidine to male mice prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats resulted in decreased weight of the testes and epididymides, decreased sperm counts, |
