Early prediction of thiopurine‐induced hepatotoxicity in inflammatory bowel disease. Issue 3 (12th December 2016)

• Record Type: Journal Article
• Authors: Wong, D. R.; Coenen, M. J. H.; Derijks, L. J. J.; Vermeulen, S. H.; van Marrewijk, C. J.; Klungel, O. H.; Scheffer, H.; Franke, B.; Guchelaar, H.‐J.; de Jong, D. J.; Engels, L. G. J. B.; Verbeek, A. L. M.; Hooymans, P. M.
• Other Names: Masclee AAM investigator.; Pierik M investigator.; Mares W investigator.; Hameeteman W investigator.; Wahab PJ investigator.; Seinen H investigator.; Rijk MCM investigator.; Harkema IM investigator.; de Bièvre M investigator.; Oostenbrug L investigator.; Bakker CM investigator.; Aquarius M investigator.; van Deursen C investigator.; van Nunen AB investigator.; Goedhard JG investigator.; Hamacher M investigator.; Gisbertz IAM investigator.; Brenninkmeijer BJ investigator.; Tan ACITL investigator.; Aparicio‐Pagés MN investigator.; Witteman EM investigator.; van Tuyl SAC investigator.; Breumelhof R investigator.; Stronkhorst A investigator.; Gilissen LPL investigator.; Schoon EJ investigator.; Tjhie‐Wensing JWM investigator.; Temmerman A investigator.; Nicolaï JJ investigator.; van Bergeijk JD investigator.; Bac DJ investigator.; Witteman BJM investigator.; Mahmmod N investigator.; Uil JJ investigator.; Akol H investigator.; Ouwendijk RJTh investigator.; van Munster IP investigator.; Pennings M investigator.; De Schryver AMP investigator.; van Ditzhuijsen ThJM investigator.; Scheffer RCH investigator.; Römkens TEH investigator.; Schipper DL investigator.; Bus PJ investigator.; Straathof JWA investigator.; Verhulst ML investigator.; Boekema PJ investigator.; Kamphuis JTh investigator.; van Wijk HJ investigator.; Salemans JMJL investigator.; Vermeijden JR investigator.; van der Werf SDJ investigator.; Verburg RJ investigator.; Spoelstra P investigator.; de Vree JML investigator.; van der Linde K investigator.; Jebbink HJA investigator.; Jansen M. investigator.; Holwerda H. investigator.; van Bentem N investigator.; Kolkman JJ investigator.; Russel MGVM investigator.; van Olffen GH investigator.; Kerbert‐Dreteler MJ investigator.; Bargeman M investigator.; Götz JM investigator.; Schröder R investigator.; Jansen JM investigator.; Bos LP investigator.; Engels LGJB investigator.; Romberg‐Camps MJL investigator.; Keulen ETP investigator.; van Esch AAJ investigator.; Drenth JPH investigator.; van Kouwen MCA investigator.; Wanten GJA investigator.; Bisseling TJ investigator.; Römkens TEH investigator.; van Vugt MWJ investigator.; van de Meeberg PC investigator.; van den Hazel SJ investigator.; Stuifbergen WNHM investigator.; Grubben MJAL investigator.; de Wit U investigator.; Dodemont GAH investigator.; Eichhorn RF investigator.; van den Brande JMH investigator.; Naber AHJ investigator.; van Soest EJ investigator.; Kingma PJ investigator.; Talstra NC investigator.; Bruin KF investigator.; Wolfhagen FHJ investigator.; Hommes DW investigator.; van der Veek PPJ investigator.; Hardwick JCA investigator.; Stuyt RJ investigator.; Fidder HH investigator.; Oldenburg B investigator.; Tan TG investigator.;
• Is Part Of: Alimentary pharmacology & therapeutics. Volume 45:Issue 3(2017)
• Page Start: 391
• Page End: 402
• Publication Date: 2016-12-12
• Subjects: Digestive organs -- Diseases -- Treatment -- Periodicals; Digestive organs -- Effect of drugs on -- Periodicals; Gastrointestinal system -- Diseases -- Treatment -- Periodicals; Gastrointestinal system -- Effect of drugs on -- Periodicals; 615.73
• DOI: 10.1111/apt.13879
• Languages: English
• ISSNs: 0269-2813

Abstract

Summary: Background: Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady‐state 6‐methylmercaptopurine ribonucleotide (6‐MMPR) metabolite concentrations. Aim: To determine the predictive value of 6‐MMPR concentrations 1 week after treatment initiation ( T1 ) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. Methods: The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised‐controlled trial evaluating pre‐treatment thiopurine S‐methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1 . Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. Results: Forty‐seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6‐MMPR threshold of 3615 pmol/8 × 10 8 erythrocytes was defined. Analysis of patients on stable thiopurine dose ( n = 174) showed that those exceeding the 6‐MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8–8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6‐MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75–0.91)]. 6‐MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4–4.3), and general malaise: OR = 2.0 (95% CI: 1.1–3.7). Conclusions: In more than 80% of patients, thiopurine‐induced hepatotoxicity could be explained by elevated T1 6‐MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure. Abstract : Linked Content This is linked to Fraser and Wong and Hooymans papers. To view these articles visithttps://doi.org/10.1111/apt.13942 andhttps://doi.org/10.1111/apt.13955 .