Optimizing thiopurine response in IBD: The clinical utility of TPMT testing and metabolite monitoring

The immunomodulatory thiopurine drugs azathioprine and 6-mercaptopurine can potentiate the therapeutic effect of corticosteroids and exert a steroid-sparing effect in patients with Crohn's disease and ulcerative colitis. However, the onset of response to the thiopurines is relatively slow, and a small proportion of patients receiving these drugs experience significant toxicities, including life-threatening leukopenia. A growing body of evidence suggests that measurement of thiopurine metabolites can help guide dosing to ensure adequate therapeutic drug levels while simultaneously reducing toxicities by minimizing the frequency of overdosing. Further, genetic polymorphisms in the thiopurine-S-methyltransferase (TPMT) enzyme, which metabolizes 6-mercaptopurine, can result in impaired TPMT activity and increase the risk of adverse events. The following roundtable discussion examines selected issues regarding the traditional use of thiopurines, thiopurine drug metabolism, TPMT testing and interpretation, utility and cost-effectiveness of metabolite monitoring, and the recent American Gastroenterological Association guidelines regarding these issues.