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P343. Skewed thiopurine metabolism leads to therapeutic failure in the majority of thiopurine using IBD patients

J.E. Kreijne1, M.L. Seinen1, A. Sinjewel2, G. Bouma1, C.J. Mulder1, A.A. van Bodegraven1, N.K.H. de Boer1, 1VU University Medical Centre, Gastroenterology and Hepatology, Amsterdam, Netherlands, 2VU University Medical Centre, Pharmacy department, Amsterdam, Netherlands

Background

The conventional thiopurines azathioprine and 6-mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued due to 6-methylmercaptopurine ribunucleotide (6-MMPR) metabolite associated refractoriness or adverse events. It is likely that patients with an aberrant thiopurine metabolism are particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in IBD patients.

Methods

Clinical effectiveness and tolerability of regular weight-based thiopurine therapy were determined in all IBD patients displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine-nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008–2012, being part of standard clinical follow-up after initiation of conventional thiopurines.

Results

Fourty-one (84%) out of 49 included IBD patients discontinued thiopurines (55% female, 53% with Crohn's disease and 47% with ulcerative colitis) with a median duration of 14 weeks (IQR 10–29). The majority of patients discontinued thiopurines due to adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was thiopurine induced hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/10e8RBC (IQR 113–218 pmol/10e8RBC), median 6-MMPR level was 11020 pmol/10e8RBC (IQR 7210–20340 pmol/10e8RBC) and the median 6-MMPR/6-TGN ratio was 72 (IQR 43–114). Thiopurine therapy failure was associated with a ratio above 50 (p < 0.03). Hepatotoxicity occurred more frequent in patients with an extreme skewed metabolism (6-MMPR/6-TGN ratio >100) (p < 0.01).

Conclusion

This study demonstrates that a skewed metabol-ism is a risk factor for early thiopurine failure in IBD patients. These observations implicate that routine thiopurine metabolite measurements can be used as a prognostic tool to identify those patients with an aberrant metabolism in an early stage, possibly benefitting from therapy adjustments.