A third phase 3 study, as yet published only in abstract form, again showed that 80 mg/d of febuxostat is superior to 300 mg/d of allopurinol (serum urate level lower than 6 mg/dL achieved by 67% and 42% of patients, respectively) and that febuxostat, 40 mg/d, and allopurinol, 300 mg/d, are equally efficacious.14 These trials also supported the notion that febuxostat is effective and safe in patients who have mild to moderate renal insufficiency (estimated glomerular filtration rate, 30 to 90 mL/min).
Because lowering serum urate levels transiently predisposes to gouty attacks, patients starting any urate-lowering therapy should receive prophylaxis for 3 to 6 months with colchicine (0.6 mg qd or bid) or, rarely, with an alternative anti-inflammatory agent. In fact, febuxostat appears to convey a greater early risk of attack than allopurinol, probably reflecting its greater urate-lowering capacity.
Although febuxostat is more potent than allopurinol on a per-molar basis and has generally outperformed allopurinol in clinical studies, it is not necessarily the superior drug. Note that virtually all the studies of febuxostat have used allopurinol as a comparator at 300 mg/d, but the latter agent is FDA-approved at up to 800 mg/d. Whether allopurinol at these higher dosages can outperform febuxostat has not been studied. However, the need to titrate allopurinol may result in a longer time to reach target serum urate levels relative to febuxostat.
Febuxostat safety and efficacy have not been assessed in patients with severe renal failure or in those who are receiving dialysis. However, clinical practice has so far supported the notion that patients with allopurinol allergies usually may take febuxostat without showing cross-reactivity.
Hyperuricemia in humans primarily is a consequence of the absence of a functional uricase enzyme. Therefore, repleting the missing enzyme via intravenous infusion is a third potential avenue for lowering uric acid. (We have reviewed the possible reasons why among all mammals, primates have a missense mutation in the uricase gene.15)
To this end, rasburicase (recombinant Aspergillus flavus uricase) was developed for the prevention or management of hyperuricemia in pediatric tumor lysis syndrome. Case reports have demonstrated the ability of rasburicase to lower serum urate levels in patients with refractory gout; however, rasburicase is highly immunogenic, and its use for more than 1 or 2 administrations may result in both the generation of neutralizing antibodies and severe hypersensitivity reactions.
Pegloticase is a recombinant, pegylated mammalian (porcine/baboon hybrid) uricase that was developed in an attempt to overcome the immune limitations of rasburicase and permit extended uricase supplementation. Pegylation (the alteration of proteins by the addition of several chains of polyethylene glycol) is an established strategy to mask the antigenicity of foreign proteins and permit their administration as therapeutic agents.
Pegloticase has been tested in replicated 6-month phase 3 trials; FDA approval currently is pending. Both trials enrolled patients who had severe gout; most had tophi and more than 6 flares per year. Most also had contraindications to allopurinol. Patients were randomized to receive 8 mg of pegloticase intravenously every 2 (n = 85) or 4 (n = 84) weeks or placebo (n = 43).
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