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Do clinical and laboratory parameters predict thiopurine metabolism and clinical outcome in patients with inflammatory bowel diseases?

  • Sven Frick
  • Daniel Müller
  • Gerd A. Kullak-Ublick
  • Alexander JetterEmail author
Pharmacodynamics
  • 27 Downloads

Abstract

Purpose

The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy failures, and it is unclear whether clinical and laboratory parameters can be used to predict thiopurine metabolite concentrations (as a surrogate for adequate remission maintenance therapy) and clinical outcome in these patients.

Methods

In this retrospective analysis of clinical routine patient data, multivariate statistical models based on Linear Mixed Models regression and Generalized Estimating Equations logistic regression were developed. The adequacy of the models was assessed using Pearson’s correlation and a receiver operating characteristic curve.

Results

This study included 273 patients and 1158 thiopurine metabolite measurements as well as routine laboratory and clinical data. In the statistical models, thiopurine metabolite concentrations and the odds of non-remission based on different clinical and laboratory parameters were computed. Correlation (r2) between predicted and measured thiopurine metabolites were 0.40 (p < 0.001) for 6-thioguanine nucleotides and 0.53 (p < 0.001) for 6-methyl-mercaptopurine nucleotides, respectively. The model for remission classified data sets in remission and non-remission with a sensitivity of 63% and a specificity of 73%. The area under the receiver operating characteristic curve of the model was 0.72.

Conclusions

Although the models are not yet accurate enough to be used in clinical routine, model-based prediction of thiopurine metabolite concentrations and of outcome is feasible. Until more accurate models are developed and validated, traditional therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel diseases under thiopurine therapy stays the best tool to individualize therapy.

Keywords

Inflammatory bowel diseases Therapeutic drug monitoring Thiopurines Azathioprine Linear and logistic regression models 

Notes

Author contribution

SF, GK-U, and AJ planned the study; SF and AJ collected the data; DM carried out the quantifications of analytes in blood; SF carried out the statistical analyses under supervision by AJ; SF wrote the first draft of the manuscript under supervision of AJ. All authors contributed to, and have approved, the final manuscript.

Compliance with ethical standards

The study was approved by the Ethics Committee of the Canton of Zurich, Switzerland (BASEC-Nr. 2017-02317).

Conflict of interest

All authors declare that they have no conflict of interest.

Supplementary material

228_2018_2616_MOESM1_ESM.docx (16 kb)
ESM 1 (DOCX 16 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Clinical Pharmacology and Toxicology, University Hospital ZurichUniversity of ZurichZürichSwitzerland
  2. 2.Institute of Clinical Chemistry, University Hospital ZurichUniversity of ZurichZurichSwitzerland

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