Azacitidine

MECHANISM OF ACTION

Azacitidine is a nucleoside analog of cytidine that works through DNA hypomethylation and direct cytotoxicity. When incorporated into DNA, it inhibits DNA methyltransferases, reactivating tumor suppressor genes that were previously silenced, which can trigger cell cycle arrest, differentiation, or apoptosis in abnormal blood cells. At higher doses, azacitidine is incorporated into RNA, disrupting RNA processing and protein synthesis, further inhibiting the proliferation of rapidly dividing malignant cells. These combined actions make azacitidine effective in treating myelodysplastic syndromes (MDS) and certain types of leukemia.

PHARMACOKINETICS

Absorption

Azacitidine is absorbed quickly after subcutaneous or intravenous administration, reaching peak plasma concentrations around 30 to 60 minutes. Subcutaneous injection provides bioavailability similar to intravenous dosing, ensuring effective systemic drug levels. Its rapid absorption supports timely onset of action in treating myelodysplastic syndromes (MDS) and certain leukemias.

Distribution

Azacitidine is widely distributed in the body, with a volume of distribution of about 8–9 L/m², indicating it mainly stays in the extracellular fluid. It binds minimally to plasma proteins (10–20%), allowing more free drug to reach target tissues, including the bone marrow, where it exerts its therapeutic effects in myelodysplastic syndromes (MDS) and leukemias.

Metabolism

Azacitidine is rapidly metabolized mainly by cytidine deaminase into inactive compounds. Part of the drug is incorporated into DNA and RNA to exert its therapeutic effects before being broken down. Its rapid metabolism results in a short plasma half-life of about 4 hours, requiring repeated dosing to maintain effective levels in treating myelodysplastic syndromes (MDS) and certain leukemias.

Elimination

Azacitidine is primarily eliminated via the kidneys as inactive metabolites, with only a small amount excreted unchanged. Its plasma half-life is approximately 4 hours, reflecting rapid clearance from the bloodstream. Renal function can influence elimination, so dose adjustments may be necessary in patients with significant kidney impairment to ensure safe and effective treatment in myelodysplastic syndromes (MDS) and certain leukemias.

PHARMACODYNAMICS

Azacitidine acts as a DNA methyltransferase inhibitorand a nucleoside analog, leadingto hypomethylation of DNA and reactivation of silenced tumor suppressor genes. This results in cell cycle arrest, differentiation, or apoptosis of abnormal hematopoietic cells. At higher concentrations, it also incorporates into RNA, disrupting RNA processing and protein synthesis, which adds a direct cytotoxic effect. These combined actions reduce the proliferation of malignant cells and improve blood cell production in myelodysplastic syndromes (MDS) and certain leukemias.

ADMINISTRATION

Azacitidine can be administered subcutaneously (SC) or intravenously (IV), depending on patient needs and clinical protocols. The subcutaneous route is most commonly used and allows for self-administration in some cases, while the intravenous route is typically reserved for patients who cannot tolerate injections or require hospital-based treatment. Dosing is usually cyclical, given daily for 5–7 days every 28 days, and may be adjusted based on tolerability, blood counts, and renal function to optimize efficacy and minimize adverse effects.

DOSAGE AND STRENGTH

Azacitidine is usually given at 75 mg/m² daily for 7 days in a 28-day cycle for myelodysplastic syndromes (MDS). It comes as a 100 mg vial of lyophilized powder for subcutaneous or intravenous use, which must be reconstituted before administration. Dosage may be adjusted for patients with kidney or liver impairment or low blood counts. Oral azacitidine, such as Onureg, is given at 300 mg daily for 14 days of a 28-day cycle for maintenance in acute myeloid leukemia (AML).

DRUG INTERACTIONS

Azacitidine can interact with drugs that affect bone marrow, increasing the risk of myelosuppression. Combining it with immunosuppressants, antiviral agents, or other cytotoxic drugs may worsen blood cell suppression. Medications that affect kidney or liver function can alter azacitidine clearance, so monitoring blood counts and organ function is recommended when used with these agents.

FOOD INTERACTIONS

Azacitidine is administered by injection (subcutaneous or intravenous), so it is not affected by food intake. No specific dietary restrictions are required, and meals do not influence its absorption or effectiveness.

CONTRAINDICATIONS

Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or any of its components. It should not be used in individuals with severe, uncontrolled infections or conditions where myelosuppression could be life-threatening without close monitoring. Caution is also advised in patients with severe renal or hepatic impairment, though these are relative contraindications and may require dose adjustments rather than complete avoidance.

SIDE EFFECTS

• Nausea and vomiting

• Diarrhea or constipation

• Fatigue and fever

• Injection site reactions (redness, pain, swelling)

• Anemia, neutropenia, thrombocytopenia (bone marrow suppression)

• Liver enzyme elevations

• Rash

• Cough

• Headache

• Rare but serious: severe infections, bleeding complications, cardiac events

TOXICITY

Azacitidine toxicity mainly affects the blood and gastrointestinal system. Common issues include anemia, neutropenia, and thrombocytopenia, which increase the risk of infection and bleeding. Gastrointestinal problems like nausea, vomiting, diarrhea, andconstipation are also frequent. Other toxicities can include liver enzyme changes, injection site reactions, and fatigue, while rare serious effects may involvesevere infections or cardiac events. Regular monitoring of blood counts and organ function helps manage these risks.