Tu1328 Final Thiopurine Metabolite Levels and Shunter Status Can Be Predicted After Six Weeks of Thiopurine Therapy - Biochemical Outcomes From the EATME Study

Abstract

Background: Dosing of thiopurines [azathioprine (AZA) and mercaptopurine (MP)] in the management of IBD has been based upon patient weight. However, this appears unreliable in predicting final levels of thiopurine metabolites, leading to suboptimal clinical outcomes because of underand over-dosing, and ‘shunting' in 15% where toxic 6-methylmercaptopurine (6MMP) is preferentially produced over the efficacious 6-thioguianine nucleotides (6TGN), with 6MMP:6TGN ratio ≥20. Aims: 1. To determine prospectively the clinical value of timing of measurement of thiopurine metabolites during dose-escalating regimen of thiopurine initiation in a consecutive cohort of IBD patients being initiated on a thiopurine. 2. To determine if the 6MMP:6TGN ratio changes during thiopurine dose escalation. Methods: In this single centre, prospective, open label study patients were commenced on either a daily dose of 50mg AZA or 25mg MP (physician discretion). Doses increased fortnightly by 50mg for AZA or 25mg for MP until target was achieved, aiming for 2-2.5mg/kg for AZA and 1-1.5mg/kg for MP. Hematology, CRP and liver function tests were performed fortnightly to monitor toxicity. Thiopurine metabolites were measured fortnightly until steady-state was achieved, but results were not used for dosing decisions. Clinical and biochemical outcomes were recorded. Landmark analyses of shunter status used logistic regression models. Metabolite levels were analysed using linear regression models. Results: 64 patients (52 Crohn's, 11 ulcerative colitis and 1 IBD-U) were enrolled. Final metabolite outcomes were: 11 (17%) patients were shunters, 27 (42%) were underdosed (6TGN level of 450) and 21 (33%) were therapeutic. 6MMP:6TGN ratios escalated over time in shunters, but not in others. After 2 weeks of therapy, a 6MMP:6TGN ratio above 9 (p=0.058) was suggestive of shunting, while after 6 weeks, a ratio ≥12 (95% CI 7-28, p=0.01) was predictive of shunting. 6TGN levels at week 2 (median 106, range 0-328) predicted final 6TGN outcomes (median282, range 50-746, r=0.681, p .10). Conclusions: 6MMP:6TGN ratios increase during dose escalation in shunters only. Patients with a 6MMP:6TGN ratio 12 or above after 6 weeks should be considered for optimisation with allopurinol rather than waiting until 12 weeks of therapy. Weight-based dosing of thiopurines should no longer be used in standard practice.