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

Aliment Pharmacol Ther 2011; 34: 544–554 Summary Background  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 i...

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Published in:Alimentary pharmacology & therapeutics 2011-09, Vol.34 (5), p.544-554
Main Authors: González‐Lama, Y., Bermejo, F., López‐Sanromán, A., García‐Sánchez, V., Esteve, M., Cabriada, J. L., McNicholl, A. G., Pajares, R., Casellas, F., Merino, O., Carpio, D., Vera, M. I., Muñoz, C., Calvo, M., Benito, L. M., Bujanda, L., García‐Fernández, F. J., Ricart, E., Ginard, D., Velasco, M., Carneros, J. A., Manceñido, N., Algaba, A., Froilan, C., Cara, C., Maté, J., Abreu, L., Gisbert, J. P.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Area Under Curve
azathioprine
Azathioprine - blood
Biological and medical sciences
Biomarkers - metabolism
Digestive system
Dose-Response Relationship, Drug
Female
Gastroenterology. Liver. Pancreas. Abdomen
Guanine Nucleotides - blood
Humans
Immunosuppressive Agents - therapeutic use
Inflammatory bowel diseases
Inflammatory Bowel Diseases - drug therapy
Inflammatory Bowel Diseases - enzymology
Male
Medical sciences
Mercaptopurine - administration & dosage
Mercaptopurine - analogs & derivatives
Metabolites
Methyltransferases - blood
Middle Aged
Other diseases. Semiology
Pharmacology. Drug treatments
Prospective Studies
ribonucleotides
ROC Curve
Steroid hormones
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Thionucleotides - blood
Toxicity
Treatment Outcome
Young Adult
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Summary:Aliment Pharmacol Ther 2011; 34: 544–554 Summary Background  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. Aim  To identify a therapeutic threshold value for TPMT or 6TGN concentrations, and their capability to predict treatment safety and efficacy. Methods  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. Results  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. Conclusions  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.
ISSN:0269-2813
1365-2036
DOI:10.1111/j.1365-2036.2011.04756.x