https://orcid.org/0009-0005-7927-5166
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Steven Trinh, Bridgette Andrew, Abhinav Vasudevan, 6-Mercaptopurine in ulcerative colitis: the potential of upfront dosing with allopurinol, Journal of Crohn's and Colitis, Volume 18, Issue 3, March 2024, Page 492, https://doi.org/10.1093/ecco-jcc/jjad150
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To the Editor
We commend Lowenberg et al. for their randomized placebo-controlled trial,1 which demonstrated that mercaptopurine was more effective than placebo in attaining clinical, endoscopic and histological improvement in patients with ulcerative colitis [UC] who had an inadequate response to 5-aminosalicylate therapy. Proactive therapeutic drug monitoring was utilized and almost half of patients in the mercaptopurine group had high 6-methylmercaptopurine [6-MMP] levels at week 6, necessitating dose reduction of mercaptopurine and the addition of allopurinol to minimize potential toxicity. Furthermore, 21% of patients had to discontinue mercaptopurine due to adverse events probably related to the study medication. This would suggest that, despite its demonstrated efficacy, tolerability of mercaptopurine remains a limiting factor in its use. Several strategies have been developed to attempt to mitigate these intolerances, including the use of allopurinol with a reduced thiopurine dose, split dosing of thiopurine therapy, and even the use of thioguanine, as this bypasses production of several metabolites associated with toxicity including 6-MMP.2
An argument could be made for upfront use of a lower dose of mercaptopurine with allopurinol, as has been demonstrated when using azathioprine therapy, for its efficacy, tolerability, and ease of dosing. A previous multicentre, open-label, randomized control trial showed that initial combination azathioprine–allopurinol therapy [0.8 mg/kg/day and 100 mg/day, respectively] was associated with higher rates of remission in moderate to severe UC compared with 2.5 mg/kg/day azathioprine monotherapy [47% vs 21%] with higher 6-thioguanine nucleotides [6-TGN] levels and lower levels of 6-MMP at weeks 6 and 52.3 No difference in rates of adverse events were found between the two groups and the doses of azathioprine and allopurinol were dependably noted to be 50 and 100 mg, respectively. A greater proportion of patients in the azathioprine–allopurinol group were in remission at week 52 and had a 6-TGN >230 pmol/8 × 108 red blood cells compared to the azathioprine group [94% vs 57%]. Previous studies have suggested that a dose of 0.4 mg/kg/day mercaptopurine with 100 mg/day allopurinol can achieve therapeutic thiopurine metabolites, which would equate to ~25 mg/day mercaptopurine.4 This dosing is convenient for patients and clinicians alike and consistently leads to favourable metabolites so can avoid the need for multiple dose adjustments.
Overall the findings of this randomized trial are important in confirming that dose-optimized mercaptopurine can achieve mucosal healing amongst patients with UC. Measures taken to potentially improve the convenience and tolerability of thiopurines, such as use of mercaptopurine with allopurinol, can make them a lower cost, safe, and effective treatment that may avoid the need for biologic therapy in some patients with UC.
Funding
No funding was received.
Conflict of Interest
The authors do not have any disclosures to report.
Author Contributions
Steven Trinh wrote the manuscript. Bridgette Andrew edited and reviewed the manuscript. Abhinav Vasudevan supervised, edited, and finalized the manuscript.
