Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

Hospital Alto Deba, Mondragón, Basque Country, Spain
Alimentary Pharmacology & Therapeutics (Impact Factor: 5.73). 07/2011; 34(5):544-54. DOI: 10.1111/j.1365-2036.2011.04756.x
Source: PubMed


Low thiopurine-methyl-transferase (TPMT) activity and high 6-thioguanine-nucleotide (6TGN) concentrations have been linked to therapeutic success in inflammatory bowel disease patients treated with thiopurines; however, this has not been implemented in clinical practice.
To identify a therapeutic threshold value for TPMT or 6TGN concentrations, and their capability to predict treatment safety and efficacy.
Prospective multicentre study including steroid-resistant/dependent patients starting thiopurines. The TPMT activity was determined at inclusion (>5 U/mL required). Azathioprine metabolites [6TGN, 6-methyl-mercaptopurine ribonucleotides (6MMP), and 6TGN/6MMP and 6TGN/TPMT ratios] were periodically monitored during steroid tapering and after withdrawal for 6 months or until a new flare occurred.
A total of 113 patients were analysed (62% clinical response). Areas under the receiver operating characteristic (ROC) curve (AUC) relating clinical response and metabolite levels at 2, 4 and 6 months after steroid withdrawal were less than 0.7. The AUCs relating final response and initial TPMT activity or metabolite concentrations at 2, 4, 8 and 16 weeks after starting thiopurines were less than 0.7. No cut-off point with worthwhile sensitivity/specificity was found. Eight (7%) patients developed thiopurine-related toxicity that could not be linked to TPMT activity or 6TGN levels.
Our results do not support determination of TPMT activity or 6TGN concentrations to predict treatment outcome, and no useful serum metabolites threshold value to adjust the drug's dose was identified.

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Available from: Javier P Gisbert, Sep 15, 2014
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    • "The activity of thiopurine methyltransferase (TPMT) and the concentration of 6-thioguanine nucleotide (6TGN) are considered to be related with the treatment of thioguanine. However, recent study does not find any relationship between them [120]. "
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    • "For example, TPMT enzyme activity was not predictive of treatment outcome a in a recent prospective trial in 113 IBD patients who started thiopurine therapy [25]. Furthermore, in both the latter study and a recent meta analysis, TPMT status was not predictive of transaminitis [10, 25]. Thus, TPMT status has limitations as a predictor of thiopurine metabolism, clinical efficacy, and adverse events. "
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