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Journal of Crohn's and Colitis: 9 (5)

Editor-in-Chief

Laurence J. Egan, Ireland

Associate Editors

Maria T. Abreu, USAShomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKGijs van den Brink, NLSéverine Vermeire, Belgium

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Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy

Lennard P.L. Gilissen , Dennis R. Wong , Leopold G.J.B. Engels , Jörgen Bierau , Jaap A. Bakker , Aimée D.C. Paulussen , Mariëlle J. Romberg-Camps , Arnold Stronkhorst , Paul Bus , Laurens P. Bos , Piet M. Hooymans , Reinhold W. Stockbrügger , Cees Neef , Ad A.M. Masclee
DOI: http://dx.doi.org/10.1016/j.crohns.2011.12.003 698-707 First published online: 1 July 2012

Abstract

Background and aims: Therapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥ 235 pmol/8 × 108 erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level.

Methods: Hundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity.

Results: Forty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263 pmol/8 × 108 erythrocytes, p = 0.29). The previous reported therapeutic 6-TGN cut-off level of 235 pmol/8 × 108 erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p = 0.04).

Conclusions: Thiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response

Keywords
  • Inflammatory bowel disease
  • Thiopurines
  • Azathioprine
  • 6-Mercaptopurine
  • Therapeutic drug monitoring
  • Non-compliance
  • Abbreviations:
    AZA
    azathioprine
    CAI
    Colitis Activity Index
    CDAI
    Crohn's Disease Activity Index
    CI 95%
    95% confidence interval
    HPLC
    high performance liquid chromatography
    IBD
    inflammatory bowel disease
    6-MMPR
    6-methylmercaptopurine ribonucleotides
    6-MP
    6-mercaptopurine
    N
    patient number
    OR
    odds ratio
    RBC
    red blood cells
    TDM
    therapeutic drug monitoring
    6-TGN
    6-thioguanine nucleotides
    TPMT
    thiopurine S-methyltransferase
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