Thioguanine (brand name Tabloid) is used to treat acute nonlymphocytic leukemias, such as acute myeloid leukemia (AML). Thioguanine is an analogue of the nucleic acid guanine and belongs to the drug class of thiopurines.
Thioguanine 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). 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 label also includes dosing recommendations for when TPMT or NUDT15, or both, genotypes are known. For individuals with a pharmacogenetic deficiency in either enzyme, the initial dose of thioguanine should be reduced, and individuals who have a deficiency in both enzymes may require more substantial dose reductions. The label notes that individuals with a complete deficiency of either enzyme often continue to require a lower dose, which is 10% or less than the standard thioguanine dose (Table 1) (1).
Dosing recommendations for thioguanine based on TPMT and NUDT15 genotype have also been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). Both the CPIC and DPWG guidelines recommend substantial dose reductions for individuals who have low or deficient enzyme activity, including considering an alternative drug to thioguanine, particularly when treating a non-malignant condition (Table 2, Table 3) (2-4).