There is no endorsement of genotyping versus activity testing.[63]

It was postulated that high TPMT phenotypic activity leads to thiopurine failure and thiopurine shunting.[2, 64] van Egmond et al. disproved this theory based on the results of 1879 patients with documented TPMT activity, 6TGN and 6MMP levels in the New Zealand national laboratory. They found 19% (n = 349) of patients were thiopurine Paclitaxel concentration shunters, with significantly higher mean TPMT levels (13.2 vs. 12.2, P ≤ 0.001), but well within the normal range. In addition, 6.9% of all thiopurine shunters had intermediate to low TPMT activity (5.0–9.2).[64] There is no consensus as to whether TPMT genotyping or TPMT phenotyping (activity testing) is the preferred test. Twenty-nine mutations in the TPMT gene have been identified, but the predominant allelic mutations vary depending on ethnicity.[3] The authors of a Swedish study of 7195 patients, including 4024 IBD patients, found that genotyping

for the three most common mutations would have DNA Damage inhibitor misclassified 8% of TPMT-deficient patients, whereas phenotyping would have misclassified 11% of patients.[66] In contrast, TPMT genotyping in 1454 French IBD patients only had a negative predictive value of 95.8% when compared to phenotyping, indicating that phenotyping is the more powerful test.[67] The advantage of genotyping is that disease state and medications cannot affect results, as highlighted by the Swedish paper that found that 43% of patients with a normal genotype, but intermediate phenotype, had a hematological disorder. Conversely, there can be a wide range of TPMT activity within a genotype. Most laboratories do not test for all mutations, which could lead to a false negative result. In theory, TPMT phenotyping may allow the physician to individualize treatment, Fludarabine manufacturer and also

predict the risk of adverse events as patients with lower TPMT activity have a higher risk for adverse events.[2] One approach might include the performance of TPMT genotyping only in patients who have low or intermediate TPMT activity levels. The initial use of AZA or 6MP is at the clinician’s discretion, as there are no useful comparative data. Pre-treatment assessment of TPMT activity to guide the initial dose and to avoid life-threatening myelosuppression from TPMT deficiency is valid, providing it does not delay treatment initiation unnecessarily. Higher doses can be initiated if TPMT activity is normal. However, it must be remembered that TPMT activity is not a perfect guide to thiopurine dosage and outcomes of metabolite results, and does not replace the need for regular blood monitoring. When TPMT testing does not take place prior to commencement of treatment, an escalating dose strategy is recommended.