Thiopurines with low-dose allopurinol (ThiLDA)—a prospective clinical one-way crossover trial
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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 100 mg 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 50 mg, 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 100 mg were switched to 50 mg for 1 month. 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 50 mg compared with 100 mg resulted in a significant decrease in mean 6-TGN levels (761 to 625 pmol/8 × 108 RBC; p = 0.005) and a significant increase in mean 6-MMP levels (451 to 665 pmol/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 50 mg allopurinol led to a decrease of 6-TGN levels compared with 100 mg allopurinol. Disease activity, side effects, and patient experience, however, were similar between allopurinol 100 and 50 mg. UC patients seem to benefit and prefer lower doses whereas the contrary is seen in CD patients.
EudraCT trial registry - number 2016-001638-84
KeywordsAllopurinol Thiopurine Metabolites Tolerability Efficacy 6-TGN 6-MMP
We thank Richard J Honeywell, Amsterdam UMC VU University Medical Center Amsterdam, Department of Medical Oncology, for his help with the enzyme assays.
The guarantor of the article is Mr. S. Faraz Chavoushi.
Specific author contributions: Mr. Chavoushi designed the research study recruited patients, collected and analyzed the data, and wrote the paper. Mrs. Malingré contributed to the design of the study, wrote the paper, and contributed to the analysis in the laboratory. Mrs. Jharap helped recruiting patients and wrote the paper. Mr. Friederich helped recruiting patients for this research study. Mr. Peters helped writing the paper and contributed to determining enzyme activities in his laboratory together with Mr. Smid.
All authors approved the final version of the manuscript.
Compliance with ethical standards
The trial was approved by the Medical Research Ethics Committees United Netherlands (MEC-U). The trial was registered in the EudraCT trial registry (https://www.clinicaltrialsregister.eu, trial number 2016-001638-84). Informed consent was obtained from all individual participants included in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
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