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P353 Are we under-recognizing skewed thiopurine metabolism in IBD patients? Routine thiopurine metabolite measurement yields clinical benefit at 12 months: A retrospective observational study.

S.-Y.J. Ooi1, M. Gounder2, R. Grafton1, P. Leach3, A. Sechi2, W. Ng2, S. Connor2, P. Bampton3, J.M. Andrews*1

1Royal Adelaide Hospital, Gastroenterology and Hepatology, Adelaide, Australia, 2Liverpool Hospital, Gastroenterology & Hepatology, Liverpool, Australia, 3Flinders Medical Centre, Inflammatory Bowel Disease Service, Bedford Park, Australia

Background

Azathioprine & 6-mercaptopurine (AZA/MP) metabolites, 6-thioguanine nucleotides (6TGN) & 6-methyl-mercaptopurine (6MMP), are measurable with a proposed "therapeutic range". Therapeutic drug monitoring (TDM) has led to the identification of "shunters" (preferential 6MMP producers), affecting ∼15% of IBD patients. Allopurinol co-therapy with reduced AZA/6MP doses overcomes skewed metabolism and can improve IBD activity. Existing studies in shunters are short term, small or focused on apparent AZA/MP resistance or hepatotoxicity. Therefore we evaluated patient outcomes ≥12 months after TDM in all "shunters" identified in a large adult IBD population.

Methods

A multi-centre, cross-sectional retrospective study was performed in 3 Australian IBD Services. Data were collected from clinical records of IBD adults, on AZA/MP for ≥4 weeks at index TDM. Patient demographics, disease characteristics, physician global assessment, IBD therapy at index TDM, and again ≥12 months after TDM-led management were collected. Therapeutic 6TGN range was defined as 235-450pmol/8x108RBC. Shunters were defined as having 6MMP:6TGN ratio ≥11.

Results

Of 343 patients, 135 (39%) shunters were identified- 102 at baseline, 33 on subsequent TDM. 91 (67%) had Crohn's disease, 76 (56%) female, & mean age 42 years. At baseline, 40 (33%) were in clinical remission, 81 (66%) had active disease. TDM was performed for proactive dose assessment (43%), ongoing active disease (27%), flare (22%) & adverse drug reactions (ADR) (7%). 12-month data was available for 122/135 shunters. Overall, TDM led to AZA/MP continuation in 23 (19%), AZA/MP-allopurinol co-therapy in 46 (38%), anti-TNFα therapy in 27 (22%), another medical agent in 9 (7%), surgery in 6 (5%). At 12 months, 90 (74%) were in clinical remission, 5 (4%) clinical improvement, 26 (21%) ongoing activity. Of 95 patients with 12-month clinical remission/improvement, 18 (19%) were managed on AZA/MP alone, whereas 40 (42%) on AZA/MP-allopurinol co-therapy were successful; 21 (22%) anti-TNFα therapy, 5 (5%) another medical agent, 6 (6%) surgery. Interestingly, clinicians only identified 85/135 shunters (63%). Of the 50 unidentified, 15 had therapeutic 6TGN/6MMP levels despite 6MMP:6TGN ≥11, 7 no change in therapy & 2 surgery, leaving 26 truly unidentified.

Conclusion

Shunters are more common than previously documented (39%) and easily unidentified. The utility of TDM in shunters extends beyond AZA/MP resistance and ADR, identifying shunters in early stages of AZA/MP therapy and with dose escalation. AZA/MP±allopurinol achieved clinical remission/improvement in 61% of patients. This is the largest study to date to evaluate ≥12 month outcomes of TDM in shunters and supports its utility throughout the course of AZA/MP therapy.