Thiopurines with low-dose allopurinol (ThiLDA)—a prospective clinical one-way crossover trial

Abstract

Many patients with Crohn's disease (CD) and ulcerative colitis (UC) who have a high 6-methylmercaptopurine/6-thioguanine (6-MMP/6-TGN) ratio receive allopurinol 100mg in addition to thiopurines to optimize metabolite concentrations. However, some patients do not tolerate allopurinol at this dosage. The aim of this study was to determine the intra-patient effect of reducing the allopurinol dosage from 100 to 50mg, in terms of metabolite concentrations, enzyme activities, efficacy, and tolerability. A prospective non-inferiority one-way crossover study was performed. CD and UC patients with stable disease using a thiopurine and allopurinol 100mg were switched to 50mg for 1month. Primary outcomes were thiopurine metabolite concentrations. Secondary outcomes were enzyme activities of xanthine oxidase, thiopurine methyltransferase and hypoxanthine-guanine phosphoribosyltransferase, disease activity, and tolerability. Twenty-two patients were included. Treatment with allopurinol 50mg compared with 100mg resulted in a significant decrease in mean 6-TGN levels (761 to 625pmol/8 × 108 RBC; p = 0.005) and a significant increase in mean 6-MMP levels (451 to 665pmol/8 × 108 RBC; p = 0.01). However, the mean metabolite concentrations were still therapeutic. Enzyme activities, disease activity scores, and patient experiences did not alter significantly. Generally, UC patients were more positive about their improved treatment than CD patients. Combination therapy with 50mg allopurinol led to a decrease of 6-TGN levels compared with 100mg allopurinol. Disease activity, side effects, and patient experience, however, were similar between allopurinol 100 and 50mg. UC patients seem to benefit and prefer lower doses whereas the contrary is seen in CD patients. EudraCT trial registry - number 2016-001638-84.