Azathioprine (brand names Imuran, Azasan) is an immunosuppressant that belongs to the drug class of thiopurines. It is used with other drugs to prevent kidney transplant rejection and to manage autoimmune and inflammatory conditions such as systemic lupus erythematosus, inflammatory bowel disease, systemic vasculitis, and rheumatoid arthritis.
Azathioprine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), the major active metabolites. The active metabolites are metabolized and inactivated by the enzyme thiopurine methyltransferase (TPMT) and the enzyme nudix hydrolase 15 (NUDT15). Thus, individuals with reduced activity of either enzyme are exposed to higher levels of thioguanine and have a higher risk of toxicity side effects, including severe bone marrow suppression (myelosuppression).
The FDA-approved drug label states that testing for TPMT and NUDT15 deficiency should be considered in individuals who experience severe bone marrow toxicities or repeated episodes of myelosuppression. The FDA recommends considering an alternative therapy for individuals who are known to have homozygous TPMT or NUDT15 deficiency, or both, and to reduce dosages for individuals who have a no function allele, cautioning that a more substantial dose reduction may be required for individuals who are either TPMT or NUDT15 poor metabolizers (Table 1) (1).
Dosing recommendations for thioguanine based on TPMT and NUDT15 genotype have also been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC, Table 2, Table 3) and the Dutch Pharmacogenetics Working Group (DPWG). Both the CPIC and DPWG guidelines recommend specific dose reductions for individuals who have low or deficient enzyme activity, including starting dose and more information on how and when to adjust the dose e.g., the time allowed to reach steady state after each dose adjustment (2-4).