Febuxostat-thiopurine combination therapy in patients with moderately severe inflammatory bowel disease

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1. BACKGROUND Febuxostat is a novel xanthine oxidase inhibitor licensed in USA, Europe and Japan for treatment of gout and other hyperuricemic disorders. There has been no attempt to license it in Australia because the market is considered too small. In Australia, the only xanthine oxidase inhibitor on the market is allopurinol. Allopurinol is an analogue of xanthine, which competitively binds xanthine oxidase. Febuxostat is not a xanthine analogue and so works by a different mechanism to competitively inhibit xanthine oxidase. The cornerstone of treatment of patients with moderately severe IBD is thiopurine therapy. Thiopurines are cytotoxic and immunosuppressive therapies originally designed for treatment of acute childhood leukemias and for organ transplantation. Patients have regular monitoring of treatment response as well as blood tests (FBC = full blood count) to ensure that there is no over-immunosuppression and that there is no excessive build-up of methylated metabolites which are hepatotoxic (therapeutic drug monitoring of thiopurine metabolites). Prof Florin and others have pioneered the combination of allopurinol – thiopurine co-therapy in IBD. The advantages of this therapy are that there the thiopurine requires a considerably lower dose (about 1/3 normal dose) to achieve a beneficial treatment outcome and there are less of its toxic methylated metabolites. Currently, there is debate about why allopurinol can result in less methylated metabolites because allopurinol has no known action on methylating enzymes. Some people think that a metabolite of allopurinol inhibits the methylation enzyme but this has not been proven. Allopurinol is generally well tolerated but there are known severe adverse drug reactions including hepatitis, fever, severe skin rash, eosinophilia and renal failure which occurs especially in Asian populations. Febuxostat is a good alternative therapy to allopurinol, but its therapeutic action when combined with thiopurines is unknown. We wish to investigate whether febuxostat – thiopurine co-therapy also works for IBD patients. 2. AIM(S) OF STUDY A pilot experiment with highly motivated patients who accumulate increased methylated metabolites on thiopurine monotreatment. 3 HYPOTHESES 3.1 The combination of thiopurine – febuxostat will allow us to use less thiopurine to effect immunosuppressive and therapeutic success. 3.2 Febuxostat will cause a reduction in methylated metabolites of thiopurines.

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