}

Azathioprine

Immunosuppressants

Drug Overview

Azathioprine (brand name Imuran) is an oral immunosuppressant in the thiopurine class. It is a prodrug converted into active thioguanine nucleotides that interfere with DNA and RNA synthesis.

This medication is used to prevent organ transplant rejection and to treat autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease (Crohn’s disease and ulcerative colitis).

Azathioprine works by inhibiting the proliferation of rapidly dividing immune cells (lymphocytes), thereby reducing inflammation and immune-mediated tissue damage.

Relevant Genes and Their Roles

Two key genes influence azathioprine response: TPMT (thiopurine S-methyltransferase) and NUDT15 (nudix hydrolase 15).

TPMT methylates and inactivates thiopurine metabolites, while NUDT15 degrades active thioguanine nucleotides to less toxic forms. Variations in these enzymes alter drug activation, clearance, and toxicity risk.

Impact of Genetics on Drug Response

Patients are categorized by TPMT and NUDT15 activity—normal, intermediate, or poor metabolizers. Lower enzyme activity leads to accumulation of active metabolites, increasing the risk of bone marrow suppression, while normal activity produces expected drug levels and standard toxicity risk.

Expected Clinical Effects of Genetic Variation

Normal Function

  • Effect on drug levels: Typical levels of active and inactive metabolites.
  • Clinical consequence: Standard immunosuppressive effect.
  • Side effects: Baseline risk of leukopenia, neutropenia, and myelosuppression.

Intermediate Function

  • Effect on drug levels: Elevated active metabolite (TGN) levels; reduced inactive metabolite (meTIMP).
  • Clinical consequence: Increased risk of bone marrow suppression.
  • Side effects: Moderate severity; more frequent leukopenia and neutropenia than normal metabolizers.

Possible Intermediate Metabolizer

  • Effect on drug levels: Moderate increase in active metabolites; reduced inactivation.
  • Clinical consequence: Similar increased risk of myelosuppression as intermediate function.
  • Side effects: Moderate severity; elevated frequency of bone marrow suppression.

Poor Function

  • Effect on drug levels: Markedly elevated active metabolite levels; little to no inactivation.
  • Clinical consequence: High risk of life-threatening myelosuppression.
  • Side effects: Severe; risk of fatal leukopenia and neutropenia without dose adjustment.

Indeterminate/Not Available

  • Effect on drug levels: Unknown impact.
  • Clinical consequence: No specific guidance; follow standard dosing with monitoring.
  • Side effects: Standard risk profile unless otherwise indicated.

Dosing Guidelines

The following dosing guidelines are based on CPIC recommendations for thiopurine therapy.

TPMT Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Normal Function Normal risk of leukopenia, neutropenia, myelosuppression Start with normal dose (2–3 mg/kg/day) and adjust based on disease-specific guidelines; allow 2 weeks to reach steady state.
Intermediate Function Higher risk of leukopenia, neutropenia, myelosuppression Start at 30–80% of normal dose (0.6–2.4 mg/kg/day) and adjust based on myelosuppression; allow 2–4 weeks to steady state.
Possible Intermediate Metabolizer Higher risk of leukopenia, neutropenia, myelosuppression Start at 30–80% of normal dose (0.6–2.4 mg/kg/day) and adjust based on myelosuppression; allow 2–4 weeks to steady state.
Poor Function High risk of severe myelosuppression; potential fatal toxicity Non-malignant: consider alternative non-thiopurine therapy.
Malignant: reduce dose 10-fold and dose thrice weekly; adjust based on myelosuppression; allow 4–6 weeks to steady state.
Indeterminate Unknown impact Initiate therapy with recommended starting dose.
Not available Unknown impact Initiate therapy with recommended starting dose.

NUDT15 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Normal Metabolizer Normal risk of leukopenia, neutropenia, myelosuppression Start with normal dose (2–3 mg/kg/day) and adjust based on disease-specific guidelines; allow 2 weeks to reach steady state.
Intermediate Metabolizer Increased risk of leukopenia, neutropenia, myelosuppression Start at 30–80% of normal dose (0.6–2.4 mg/kg/day) and adjust based on myelosuppression; allow 2–4 weeks to steady state.
Possible Intermediate Metabolizer Increased risk of leukopenia, neutropenia, myelosuppression Start at 30–80% of normal dose (0.6–2.4 mg/kg/day) and adjust based on myelosuppression; allow 2–4 weeks to steady state.
Poor Metabolizer High risk of severe myelosuppression Non-malignant: consider alternative non-thiopurine therapy.
Malignant: reduce dose 10-fold and adjust based on myelosuppression; allow 4–6 weeks to steady state.
Indeterminate Unknown impact Initiate therapy with recommended starting dose.
Not available Unknown impact Initiate therapy with recommended starting dose.

Alternative Treatment Options

For patients with poor TPMT or NUDT15 function, CPIC guidelines suggest considering alternative non-thiopurine immunosuppressants (for example, mycophenolate mofetil or methotrexate) rather than azathioprine.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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