DRUG EVALUATION Febuxostat: a safe and effective therapy for hyperuricemia and gout Natasha Jordan† & Febuxostat is a novel, nonpurine, selective xanthine oxidase inhibitor and is a potential Geraldine M McCarthy alternative to allopurinol for patients with hyperuricemia and gout. Unlike allopurinol, which †Author for correspondence undergoes renal elimination, febuxostat is metabolized via hepatic conjugation and Mater Misericordiae oxidation. Phase III studies have shown that febuxostat, at a once-daily dose of 80, 120 or University Hospital, Eccles St. Dublin 7, Ireland 240 mg (safety dose), is more effective than allopurinol (300 mg) in reducing and Tel.: + 35 316 405 514; maintaining serum urate concentrations lower than 6 mg/dl. Reductions in gout flares and [email protected] tophus areas with febuxostat treatment are similar to those occurring with allopurinol therapy. Patients with moderate renal impairment can achieve significant serum urate reductions, without dose adjustments. Therefore, febuxostat represents a viable treatment choice, with documented efficacy and safety in hyperuricemia and gout. Gout is a disease in which tissue deposition of agents) or by decreasing urate synthesis (xan- monosodium urate crystals occurs as a result of thine oxidase inhibitors). These therapeutic hyperuricemia, defined as a serum urate concen- options are not without their limitations. tration that exceeds the limit of solubility (∼6.8 mg/dl [400 µmol/l]). Clinical manifesta- Market overview tions include recurrent attacks of acute inflam- Allopurinol is a competitive inhibitor of xanthine matory arthritis, accumulation of urate crystals oxidase, preventing the oxidation of xanthine to in the form of tophaceous deposits and nephro- uric acid. Allopurinol and its active metabolite, pathy. Despite advances in our understanding of oxipurinol, are structural analogs of hypoxanthine the pathogenesis of gout and the availability of and xanthine, respectively [7]. As oxipurinol is allopurinol for approximately 50 years, hyper- excreted primarily by renal mechanisms, its half- uricemia and its sequelae are not only prevalent, life is prolonged in renal failure, necessitating a but the incidence and costs associated with this reduction in allopurinol dosage. The most com- disorder continue to increase [1]. monly used dose of allopurinol is 300 mg daily. Epidemiological studies suggest that the over- There is considerable variation in the daily dose all burden of gout is substantial and growing. required to control serum urate levels, ranging The prevalence of gout and clinically significant from 100 to 800 mg and more [8]. The most con- hyperuricemia is increasing in both sexes over cerning and potentially life-threatening adverse the age of 65 years. Males still carry most of the event is allopurinol hypersensitivity syndrome, burden of disease [2]. Lifestyle and dietary factors consisting of an erythematous rash, fever, hepati- may explain the increasing incidence of gout [3]. tis, eosinophilia and renal failure [9,10]. Renal dys- Obesity and weight gain are strong risk factors function appears to be a risk factor in the for gout in men, while weight loss is protective. development of allopurinol hypersensitivity syn- Hypertension and diuretic use are also important drome. Avoidance of allopurinol or use of reduced independent risk factors for gout. Higher levels doses in patients with renal insufficiency may of meat and seafood consumption are associated reduce the incidence of allopurinol toxicity [11]. with an increased risk of gout, whereas a higher Patients with allopurinol-induced maculopapular consumption of dairy products is associated with eruptions have been successfully managed with a decreased risk [4,5]. Alcohol intake is strongly slow oral desensitization, temporary withdrawal associated with an increased risk of gout. This of the drug and subsequent reintroduction with risk varies substantially according to type of alco- dosage adjustment [12]. holic beverage. Beer confers a larger risk than The potential drug interactions between Keywords: febuxostat, gout, hyperuricemia, renal safety spirits, whereas moderate wine drinking does not allopurinol and azathioprine or 6-mercaptopu- increase the risk [6]. Currently available treat- rine must be considered. Both drugs are partly ments of hyperuricemia in patients with gout metabolized by xanthine oxidase, thus inhibition reduce serum urate concentration either by of this enzyme by allopurinol may increase their enhancing renal excretion of uric acid (uricosuric immunosuppressant and toxic effects. 10.2217/17460816.1.3.303 © 2006 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2006) 1(3), 303–309 303 DRUG EVALUATION – Jordan & McCarthy Poor compliance is a drawback of allopurinol Figure 1. Febuxostat and allopurinol. therapy. A recent, large, retrospective study of patients with gout who were prescribed allopuri- CH nol showed noncompliance with therapy for an 3 OH average of 44% of their treatment periods over N 2years [13]. Febuxostat S A series of 1-phenypyrozoles have demon- O strated xanthine oxidase inhibitory activity. The CH 3 N most potent of these, Y-700, has been evaluated in O N N healthy male volunteers. It decreased serum uric N CH3 acid in a dose- and time-dependent manner. It is Allopurinol eliminated predominantly via the liver, thus it may N O be safe in patients with renal failure. However, it remains under investigation at this time [14]. The uricosuric drugs are weak organic acids Chemistry that promote renal clearance of uric acid by Febuxostat is a thiazolecarboxylic acid derivative. inhibiting the urate–anion exchanger in the prox- It is described chemically as 2-[3-cyano-4- imal tubule that mediates urate reabsorption [15]. (2-methylpropoxy)-phenyl]-4-methylthiazole-5- The use of uricosuric agents, such as probenecid carboxylic acid. It is also known as TEI-6720 or or sulfinpyrazone, is limited in patients with renal TMX-67. It does not structurally resemble insufficiency. Other limitations of their use are purines or pyrimidines, unlike allopurinol, the need for multiple daily doses, potential drug which is a purine-based analog [21]. interactions and the risk of nephrolithiasis. Losartan, an angiotensin II receptor antago- Pharmacodynamics nist, has been shown to increase urinary uric acid Febuxostat is a potent xanthine oxidase and xan- excretion and hence lower serum uric acid thine dehydrogenase inhibitor, but has minimal levels [16]. A combination of losartan and fenofi- effects on other enzymes involved in purine and brate reduces serum uric acid concentrations fur- pyrimidine metabolism, in contrast to ther, with a concomitant increase in uric acid allopurinol [22–25]. It exhibits potent mixed-type excretion. Fenofibrate alone reduces plasma uric inhibition of both the oxidized and reduced forms acid concentration; however, the effect is weak of xanthine oxidase. This mechanism is mediated when compared with combination therapy [17]. by high-affinity binding of febuxostat to the Further studies are required to ascertain the use- enzyme in a molecular channel leading to the fulness of combined losartan and fenofibrate in molybdenum–pterin active site. The binding of the treatment of hyperuricemia and gout. febuxostat to xanthine oxidase persists, independ- Uricase (urate oxidase) is a novel therapy for ent of the redox state of the molybdenum cofactor, reduction of serum uric acid levels. Uricase cat- and blocks substrate access to the active site. The alyzes the conversion of urate to a more soluble enzyme inhibitor complex is stable and not influ- molecule, allantoin. Uricase is present in most enced by changes in the redox status of the cofactor, mammals, but absent in humans due to a muta- in contrast to the oxypurinol-inhibited enzyme. tional inactivation of uricase genes. Preliminary This allows for lower therapeutic doses [22,23]. efficacy and safety data from single infusions of pegylated uricase have been reported [18,19]. The Pharmacokinetics & metabolism development of antipegylated uricase antibod- Following its oral administration in healthy ies has been documented and may limit efficacy human subjects, febuxostat is absorbed rapidly, in some patients [20]. Further studies are needed with a maximum absorption time of approxi- to assess the immunogenicity and long-term mately 1 h. The drug is highly bound to albumin safety of pegylated uricase in the treatment of in blood (∼90%) and appears to have a low-to- hyperuricemia and gout. medium volume of distribution of approximately 0.7 l/kg. Daily febuxostat doses in the range of Introduction to the compound 10–120 mg resulted in proportional mean serum Febuxostat is an oral, once daily, selective non- urate reductions ranging from 25 to 70%, and purine xanthine oxidase inhibitor. A comparison proportional increases in maximum febuxostat of the structure of febuxostat with allopurinol is plasma concentrations and the area under plasma shown in Figure 1. concentration versus time curves in healthy 304 Future Rheumatol. (2006) 1(3) Febuxostat – DRUG EVALUATION adults. Febuxostat is metabolized mainly in the Pivotal Phase III trial liver to acyl-glucuronide metabolites and, to a The Febuxostat versus Allopurinol Controlled lesser extent, to oxidative metabolites by Trial (FACT), a Phase III, randomized, double- cytochrome P450 enzymes [26]. blind trial, compared the safety and efficacy of Single-dose febuxostat administered to sub- febuxostat with that of allopurinol