Dr Friedman
Many IBD patients who are intolerant or unresponsive to thiopurines can have good clinical responses if the drugs are used in low doses combined with allopurinol, Victorian clinicians have shown.
Allopurinol favours production of the active metabolite 6TGN (thioguanine nucleotides) from IBD drugs such as azathioprine and mercaptopurine over the inactive thiopurine metabolite 6MMP that is associated with toxicity.
And in a multicentre study led by Dr Antony Friedman, gastroenterologist in the Department of Gastroenterology at The Alfred Hospital and Monash University, Melbourne, low-dose combination of allopurinol and thiopurine safely reversed the ‘shunting’ effect seen in thiopurine hypermethylaters and enabled good disease responses to be achieved.
In the prospective, double blind trial in 73 patients with active, steroid-dependent IBD and thiopurine shunting, 39 achieved steroid-free remission and 81% were able to discontinue steroids.
The clinical benefits were seen as early as week two, presumably due to the rapid rise in levels of 6TGN. Patients showed optimised levels of the active metabolite 6TGN and had greater metabolite stability with doses of 100mg daily of allopurinol.
Despite concerns about adverse effects such as myelotoxicity, the low dose allopurinol-thiopurine treatment was generally well tolerated, with three patients on doses of 50mg/day having transient leucopenia.
Dr Friedman and colleagues noted that in current practice up to 60% of patients did not respond to weight based thiopurine doses and up to 40% would have an adverse event leading to drug cessation.
“These findings, combined with the marked reduction in steroid requirement, confirmed a reduction in the inflammatory burden of disease for patients,” they stressed.
They said their findings showed that good outcomes could be achieved when dosing was individualised according to a patient’s thiopurine metabolite results rather than their weight.
“This advance in clinical pharmacology has significant implications for physicians who use thiopurines in the management of IBD,” they wrote in Alimentary Pharmacology and Therapeutics.