Can We Improve on Allopurinol? New Xanthine Oxidase Inhibitors Under Study

While allopurinol is presently the gold standard in the treatment of gout, its problems are manifold. If either of the new xanthine oxidase inhibitors described at this year's ACR meeting hold up in safety and efficacy as Phase III trials are completed, they may, at a minimum, provide an alternative for patients presently unable to take allopurinol. If their performance is excellent in further study, one or both may even take over the role of "drug of choice" in patients who require urate lowering.

Allopurinol is essentially the only option in the U.S. to treat urate over-producers. Despite the availability of probenecid, allopurinol remains the drug most used in under-excretors as well. Although allopurinol is the "drug of choice," it is far from ideal. Allergy to allopurinol is not rare, most commonly presenting with rash. Unfortunately, more severe reactions also occur, including liver function test abnormalities. The most feared complication of allopurinol is termed the "allopurinol hypersensitivity syndrome," which presents with fever, vasculitic or bullous skin lesions, and hepatic dysfunction - and may be fatal.

Treatment of patients with allergy to allopurinol has been problematic. Intravenous and oral regimens for desensitization have been described on this site, but these do not work for all patients, and the intravenous desensitization route has been associated with anaphylaxis.

In addition, significantly higher rates of allopurinol toxicity have been described in patients with renal insufficiency, likely at least in part due to serum build-up of allopurinol's primary metabolic breakdown product, oxypurinol (which has a primarily renal route of excretion). This has led many experts to advise keeping allopurinol doses low in patients with decreased creatinine clearance, which often leaves patients with high serum urate (and continuing problems with gout and/or renal stones).

Two new agents being studied show some promise of avoiding some of the problems of allopurinol.

Febuxostat is a non-purine xanthine oxidase inhibitor, which would not be expected to cross-react with allopurinol, and so should be acceptable in allopurinol-allergic patients.[1],[2] Febuxostat appears to be more specific for xanthine oxidase than allopurinol - and the abstract by Zhao et al[1] found no inhibition of other enzymes of purine and pyrimidine metabolism with this new agent (such as HGPRTase or guanine deaminase). This could turn out to be associated with fewer side-effects. A phase II dose-response study was described by Kamatani et al[2] showing effective dose-related urate lowering. The drug was generally well-tolerated.

Y-700 is a xanthine oxidase inhibitor which has minimal urinary excretion of unchanged drug, and metabolites were observed in plasma at levels much lower than the unchanged drug.[3] This suggests that Y-700 would avoid the problems of serum level build-up in patients with renal insufficiency, and could allow full doses to be given to such patients. Noma et al[4] reported on a Phase I trial, looking at 12 men receiving 60mg qd of Y-700 and 12 receiving 120mg. A marked and dose-related lowering of serum urate was noted by day 4, with no serious adverse effects.

Both of the agents described at the 2003 ACR meeting are promising as alternatives to allopurinol. We are presently in a difficult situation with gout patients with allopurinol allergy or intolerance, and in those with renal insufficiency. Hopefully, Febuxostat will move to Phase III trials shortly, and Y-700 will enter Phase II trials.

Prior reports have shown a steady increase in the number of reported cases of gout. "Among men and women 20 years and older....2.7% (5.1 million) reported a diagnosis of gout by a physician."[5] With the incidence this high, the number of patients who need, but are poor candidates for, allopurinol will only increase with time. New, and different, xanthine oxidase inhibitors would be a major advance.