An integrated triple approach – TPMT phenotype, NUDT-15 genotype, and therapeutic drug monitoring of thiopurine metabolites for optimal clinical efficacy: a case series

Thiopurines, a widely used immunosuppressant for autoimmune and inflammatory condition, is associated with potentially severe adverse effects, particularly myelosuppression. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) can largely predict the risk of thiopurine-induced toxicity. Therapeutic drug monitoring (TDM) of its metabolites, particularly 6-thioguanine nucleotides (6-TGN), may help to optimize dosing and prevent toxicity. A case series of four Indian patients who developed azathioprine-related myelosuppression is presented. Each patient either expressed a low to intermediate TPMT enzyme activity or a NUDT15 c.415C>T (p.R139C) polymorphism. In all cases, 6-TGN concentrations were measured to assess thiopurine exposure. TPMT phenotyping, NUDT15 genotyping, and 6-TGN monitoring represents an integrated approach to optimize thiopurine therapy.