Chemical formula: C₈H₁₂N₄O₅ Molecular mass: 244.205 g/mol PubChem compound: 9444
Azacitidine is a DNA methyltransferase inhibitor and epigenetic modifier. Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates. Incorporation of azacitidine into the DNA of AML cells, modified epigenetic pathways through the inhibition of DNA methyltransferases, and reduction of DNA methylation. This led to alteration of gene expression, including re-expression of genes regulating tumour suppression, immune pathways, cell cycle, and cell differentiation. Incorporation of azacitidine into the RNA of AML cells, inhibited RNA methyltransferase, reduced RNA methylation, decreased RNA stability, and decreased protein synthesis.
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.
Non-proliferating cells are relatively insensitive to azacitidine.
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 (Cmax) of subcutaneous admiminstration of azacitidine were approximately proportional within the 25 to 100 mg/m² dose range.
Exposure was generally linear with dose-proportional increases in systemic exposure; high intersubject variability was observed. The geometric mean (coefficient of variation [%CV]) Cmax and AUC values after oral administration of a 300 mg single dose were 145.1 ng/mL (63.7) and 241.6 ng h/mL (64.5), respectively. Multiple dosing at the recommended dose regimen did not result in drug accumulation.
Absorption of azacitidine was rapid, with a median Tmax of 1 hour post dose. Mean oral bioavailability relative to subcutaneous (SC) administration was approximately 11%.
The impact of food on the exposure of azacitidine was minimal. Therefore, azacitidine can be administered with or without food.
Following intravenous administration, the mean volume of distribution was 76 ± 26 L, and systemic clearance was 147 ± 47 L/h.
After oral administration, the geometric mean apparent volume of distribution was 12.6 L/kg for a 70 kg person. The plasma protein binding of azacitidine was 6 to 12%.
Based on in vitro data, azacitidine metabolism does not appear to be 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. 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 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) azacitidine up to 100 μM did not produce inhibition. Therefore, CYP enzyme induction or inhibition by azacitidine at clinically achievable plasma concentrations is unlikely.
Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t1⁄2) 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 14 C-azacitidine, 85 and 50 % of the administered radioactivity was recovered in urine respectively, while <1% was recovered in faeces.
The geometric mean apparent clearance was 1242 L/hour and the geometric mean half-life was approximately 0.5 hours. Following intravenous administration of 14C azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Faecal excretion accounted for <1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following subcutaneous administration of 14C-azacitidine was 50%. The amount of unchanged azacitidine recovered in urine relative to dose was <2% following either subcutaneous (SC) or oral administration. Faecal excretion has not been measured following oral administration.
The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been formally studied.
Renal impairment has no major effect on the pharmacokinetic exposure of azacitidine after single and multiple subcutaneous administrations. Following subcutaneous administration of a single 75 mg/m² dose, mean exposure values (AUC and Cmax) from subjects with mild, moderate and severe renal impairment were increased by 11-21%, 15-27%, and 41-66%, respectively, compared to normal renal function subjects. However, exposure was within the same general range of exposures observed for subjects with normal renal function. 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.
The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not been formally investigated.
In a population pharmacokinetics (PK) analysis from 286 AML patients, age (46 to 93 years) did not have clinically meaningful effects on the PK of azacitidine. Therefore, dose modification for azacitidine is not required, regardless of patient age.
No formal studies have been conducted in patients with hepatic impairment. Hepatic impairment is unlikely to affect the PK to a clinically relevant extent since azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. A population PK analysis determined that AST (8 to 155 U/L), ALT (5 to 185 U/L) and mild hepatic impairment (BIL ≤ ULN and AST > ULN, or BIL 1 to 1.5 × ULN and any AST) did not have clinically meaningful effects on the PK of azacitidine. The effects of moderate to severe hepatic impairment (BIL >1.5 × ULN and any AST) on the PK of azacitidine is unknown.
In patients with cancer, the PK of azacitidine in 6 patients with normal renal function (CLcr >80 mL/min) and 6 patients with severe renal impairment (CLcr <30 mL/min) were compared following daily subcutaneous dosing (Days 1 through 5) at 75 mg/m²/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events.
A population PK analysis following a 300 mg dose of azacitidine determined that patients with mild (CLcr: ≥60 to <90 mL/min), moderate (CLcr: ≥30 to <60 mL/min), and severe (CLcr: <30 mL/min) renal impairment had 19%, 25%, and 38% increases in azacitidine plasma AUC, respectively. The effect of severe renal impairment on azacitidine was similar to the above referenced clinical renal impairment study with injectable azacitidine (~40% increase in AUC). The exposure of azacitidine (AUC) is approximately 75% lower after oral administration relative to the exposure achieved following SC administration; therefore, an increase in exposure of approximately 40% following oral administration is still considered safe and tolerable. Thus, no dose adjustment of azacitidine is recommended in patients with mild, moderate, or severe renal impairment.
The effects of race/ethnicity on the PK of azacitidine is unknown.
In a 14-day oral toxicity study in dogs, mortality occurred at doses of 8 and 16 mg/m²/day. The maximum tolerated dose (MTD) was 4 mg/m²/day. At 1 or all doses, pancytopenia correlated with bone marrow hypoplasia, lymphoid depletion, gland/lumen dilation and single cell necrosis in mucosal crypts of small and large intestines and/or centrilobular hepatocellular vacuolation were observed. At the MTD, these findings were partially or completely resolved after 3 weeks. Following parenteral azacitidine administrations at comparable dose ranges, mortality and similar target organ toxicities were observed in rodents, dogs and monkeys. Non-clinical data from repeat-dose toxicity studies with azacitidine revealed no special hazard for humans.
Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammalian cell systems in vitro. The potential carcinogenicity of azacitidine was evaluated 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 reactions when given pre- implantation, but it was clearly embryotoxic when given during organogenesis.
Foetal abnormalities during organogenesis in rats included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly) and others (microphthalmia, 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, decreased pregnancy rates, an increase in abnormal embryos and increased loss of embryos in mated females.
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