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The past decade has witnessed an exponential increase of novel therapeutic modalities for a variety of rheumatic disorders, including gout. During the past few years two novel therapeutic agents have been approved by the US Food and Drug Administration for the treatment of hyperuricemia in patients with gout, one of them being febuxostat, a nonpurine selective inhibitor of xanthine oxidase. Review of its pharmacokinetics and pharmacodynamics, efficacy and safety profile, and use in gout patients with comorbid conditions reveals that age and gender have no clinically significant effect and dose adjustments based on age or gender are not required. In addition, febuxostat can be used in patients with mild-to-moderate renal or hepatic involvement. Its overall efficacy and safety profile is comparable and, in certain subsets such as gout patients with mild and moderate renal insufficiency, is superior to allopurinol.
Gout and hyperuricemia are important disorders because they are highly prevalent and have treatment implications beyond the care of inflamed joints. In addition, these disorders are of great interest for investigators and clinicians because of the newly recognized pathogenic mechanisms underlying the disorders, and for the development of newer therapeutic modalities.
The Egyptians recognized gouty arthritis more than 2000 years BC, and Hippocrates, Galen, and Sydenham provided subsequent, highly detailed descriptions [Nuki and Simkin, 2006]. Through its history, gout has been associated with overindulgence, alcohol consumption, and with a lifestyle that, in the past, was considered only to be available to wealthy people; it was once considered ‘the disease of kings’.
In recent years, substantial advances have been made in elucidating the molecular and genetic mechanisms of the underlying inflammatory process, the role of comorbid disorders, and the clinical response to therapy [Ghaemi-Oskouie and Shi, 2011; Choi et al. 2010; Riches et al. 2009; Dehghan et al. 2008; Martinon et al. 2006]. The intimal molecular mechanism(s) by which monosodium urate crystals induce inflammation has been elucidated. It has been clearly shown that monosodium urate engages the caspase-1-acti-vating NALP3 (or cryopyrin) inflammasome, leading to the production of active interleukin 1β and interleukin 18 [Ghaemi-Oskouie and Shi, 2011; Martinon et al. 2006]. Genome-wide association studies performed in large populations of diverse ethnic backgrounds, including Whites and African Americans, have shown several genetic loci associated with uric acid concentration and gout [Choi et al. 2010; Riches et al. 2009; Dehghan et al. 2008].
This review summarizes recent progress in the development of newer therapeutic strategies for the management of the hyperuricemia of gout, particularly in the development of febuxostat, a urate-lowering agent.
The incidence and prevalence of gout and hyper-uricemia are increasing worldwide secondary to a multitude of factors, especially changes in dietary intake and lifestyle, in both developed and developing countries. Better recognition of risk factors has also contributed to this increase in the incidence and prevalence of these disorders, including older age, particularly in women, patients with coexisting severe heart failure or chronic renal disease, and the presence of comorbid conditions such as hypertension, diabetes, cardiovascular disease, and metabolic syndrome [Chiou et al. 2010; Mazzali et al. 2010; Feig, 2009; Weaver, 2008].
It is estimated that the incidence and prevalence of gout and hyperuricemia in the USA are over 6 and 42 million, respectively, with a progressively increasing pattern and affecting mainly men over the age of 40 years, and in whom it is the most frequent form of inflammatory joint disease [Lawrence et al. 2008; Choi et al. 2007].
Gout is characterized by hyperuricemia exceeding 6.8 mg/dl, the upper limit of urate solubility, and by the acute and chronic clinical consequences of urate crystal deposition, which results in episodic gout flares, tophus deposition, renal uric acid deposition, and deforming and destructive arthropathy.
Therapeutic management of gout has gained increasing attention in recent years as new therapeutic agents have become available for long-term use. Management aims to reduce serum uric acid (sUA) below 6.0 mg/dl (357 μmol/l), which, according to several consensus reports and recommendations, decreases the risk of recurrent attacks and tophus formation [Sundy, 2010; Terkeltaub, 2010; Zhang et al. 2006].
Urate-lowering therapy (ULT) for asymptomatic hyperuricemia is a topic of great interest and importance, and is currently the subject of intense discussion. Recently recognized associations between hyperuricemia, hypertension (especially in children), obesity, and aging have provided an incentive to develop alternative strategies of treating hyperuricemia [Feig et al. 2008]. ULT for asymptomatic hyperuricemia is not approved in the USA or Europe. However, recently introduced guidelines for the management of gout and hyperuricemia in Japan consider treatment of asymptomatic hyperuricemia (AHU) when the sUA is higher than 8 mg/dl, as prophylaxis for gouty arthritis, cardiovascular disease, and renal dysfunction [Nakaya et al. 2011].
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine during symptomatic gouty attacks has proven beneficial in most patients, but they do not have any effect on sUA levels. In patients exhibiting persistent gouty attacks, maintenance therapy with ULT (xanthine oxidase inhibitors, uricase analogs, and uricosuric agents) is necessary to prevent further attacks. ULT has proven to be effective if administered long-term on a regular basis to achieve a targeted sUA level of 6 mg/dl, although lower serum levels may be needed to promote effective tophus resorption [Schlesinger et al. 2009; Wortmann and Schumacher, 2005].
At present, three classes of drug are approved for lowering urate levels: xanthine oxidase inhibitors, uricosuric agents, and uricase agents (Table 1).
Xanthine oxidase inhibitors block the synthesis of uric acid, which is usually achieved through two enzymes: xanthine oxidase and xanthine dehydrogenase (Figure 1). In this class of drugs, allopurinol was the most common agent used, mostly because it was the only available agent in its class, and it became the most frequently prescribed ULT. Allopurinol functions as both a substrate and inhibitor of xanthine oxidase and, by contrast with some uricosuric agents, with dose adjustment it can be used in patients with renal impairment [Chao and Terkeltaub, 2009].
Febuxostat is the most recent urate-lowering drug approved by the FDA for the treatment of chronic hyperuricemia in patients with gout. Unlike allopurinol (and its active metabolite oxypurinol), febuxostat is not a purine analog and inhibits only xanthine oxidase/dehydrogenase, not other enzymes in the purine and pyrimidine metabolic pathways [Edwards, 2009; Khosravan et al. 2006b; Okamoto et al. 2003]. In vitro studies have demonstrated how febuxostat potently and selectively inhibits human xanthine oxidase activity, whereas the activity of other enzymes, such as purine nucleoside phosphorylase, adenosine deaminase, and pyrimidine nucleoside phosphorylase, are affected by less than 4% [Yamamoto et al. 2000].
Preclinical studies demonstrated that febuxostat was more potent than allopurinol in inhibiting xanthine oxidase and decreasing sUA levels. In vitro, drug concentrations that achieved 50% inhibition of the activity of both enzymes were much lower for febuxostat than allopurinol in different substrates (bovine milk, mouse and rat liver). In vivo, administration of febuxostat to chimpanzees at 24, 48, and 72 h decreased sUA levels twofold more than allopurinol [Becker et al. 2004; Osada et al. 1993].
Febuxostat is well absorbed after oral administration, with an estimated 80% absorption, and no clinically relevant effect has been found for food or antacids on its absorption [Khosravan et al. 2008a]. Febuxostat is primarily metabolized in the liver, and is eliminated by hepatic pathways and, to a lesser degree, renal pathways [Khosravan et al. 2006a]. The pharmacokinetics are not affected in subjects with mild-to-moderate hepatic impairment and no dose adjustments are required in mild-to-moderate renal impairment (creatinine clearance 30–80 ml/min).
The safety and efficacy of febuxostat has not been fully evaluated in gout patients with creatinine clearance less than 30 ml/min, and no significant age or gender effects on pharmacokinetics have been shown [Khosravan et al. 2008b; Mayer et al. 2005]. A recent observation, however, has shown that maintenance or improvement in glomerular filtration rate (eGFR) was correlated with the quantitative reduction of sUA from baseline. For every 1 mg/dl decrease in sUA, the model projected an expected improvement in eGFR of 1 ml/min from the untreated value. The authors concluded that individuals with the greatest reduction in sUA might experience reduced rates of renal deterioration, or even stabilization of renal function [Whelton et al. 2011].
Further studies examining the impact of long-term ULT on renal function in hyperuricemic gout patients are needed to both confirm these results and verify if improvements in renal function are feasible in such patients.
Febuxostat has been extensively studied with more than 4000 patients investigated in one phase II clinical trial and three phase III randomized controlled trials, some of them followed for over 5 years (Table 2).
The first phase II randomized double-blind dose-response study was performed in 153 patients with chronic gout in which febuxostat 40, 80 and 120 mg/day were compared with placebo over a period of 28 days, using colchicine as prophylaxis in all groups [Becker et al. 2005a].
The primary endpoint was the proportion of patients achieving a sUA level of <6.0 mg/dl on day 28. Greater proportions of febuxostat-treated patients achieved the primary endpoint with statistical significance (p < 0.001 for each comparison), in 0% of patients on placebo and in 56% of patients taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg. Secondary endpoints included the mean sUA reduction from baseline to day 28, which was 2% in the placebo group, 37% in those on 40 mg, 44% in the 80 mg group, and 59% in the 120 mg group. Gout flares occurred with similar frequency in the placebo and 40 mg groups (37% and 35%, respectively) and at higher frequency in the higher doses of febuxostat: 43% at 80 mg and 55% in the 120 mg group. The safety profiles for febuxostat and placebo were similar, as treatment-related adverse events did not show differences among placebo and the three groups of febuxostat.
The phase II trial was followed by the FOCUS clinical trial (Febuxostat Open Label of Urate-Lowering Efficacy and Safety) as an extension study. A total of 116 patients were enrolled and some of them were followed for more than 5 years [Schumacher et al. 2009]. The results of the FOCUS trial are discussed later in this review.
The phase III randomized allopurinol comparison clinical trials were FACT (Febuxostat versus Allopurinol Controlled Trial) a 52-week doubleblind study of 760 patients, APEX (Allopurinol Placebo-Controlled Efficacy Study of Febuxostat) a 28-week, double-blind, placebo-controlled study of 1072 patients, and CONFIRMS a phase III double-blind randomized controlled trial that further examined the comparative urate-lowering efficacy and safety of febuxostat and allopurinol in a larger number of patients (2269) followed for 6 months [Becker et al. 2010; Schumacher et al. 2008; Becker et al. 2005b].
The EXCEL clinical trial (Febuxostat Comparative Extension Long-Term Study) was a long-term nonblinded extension study in patients completing FACT and APEX, involving 1086 patients [Becker et al. 2009].
In the FACT trial, 760 patients with gout and a sUA >8.0 mg/dl were randomly assigned to receive either febuxostat 80 or 120 mg or allopurinol 300 mg once daily for 52 weeks. Prophylaxis with naproxen or colchicine for acute flares was provided during the first 8 weeks. The primary endpoint was the proportion of patients to achieve a sUA concentration below 6.0 mg/dl at the last three monthly measurements. Secondary endpoints included reduction in the incidence of acute flares and tophus area [Becker et al. 2005b].
The primary endpoint was achieved in 53% of patients receiving 80 mg febuxostat, 62% of patients receiving 120 mg and 21% of those receiving allopurinol (p < 0.001 for each febuxostat group compared with allopurinol). There were no significant differences noted in secondary endpoints between groups. A significant number of patients in both febuxostat groups were discontinued from the study compared with the allopurinol group, and four deaths occurred in both febuxostat groups, compared with none in the allopurinol group, but the deaths were not considered to be drug related [Lustberg, 2006; Becker et al. 2005b]. The higher rate of discontinuation in the febuxostat groups was due to the higher incidence of loss to follow-up, adverse events, and gout flares. Abnormal liver function test results led to the withdrawal of five patients receiving 80 mg febuxostat, seven receiving 120 mg febuxostat, and one receiving allopurinol [Becker et al. 2005b].
The APEX trial was a head-to-head phase III controlled clinical trial for gout, with a total of 1072 patients with sUA levels higher than 8.0 mg/dl. Patients were randomized to a once-daily fixed dose of placebo; febuxostat 80 mg, 120 mg, or 240 mg; or allopurinol 300 mg or 100 mg, depending on their baseline serum creatinine (≤ 1.5 mg/dl or ≥1.6 to <2.0 mg/dl, respectively). The primary endpoint for the trial was the proportion of subjects with sUA levels below 6.0 mg/dl at each of the last three visits [Schumacher et al. 2008].
After 1 year of treatment, 82% of the patients in all febuxostat groups achieved sUA levels below 6.0 mg/dl, compared with 39% of the patients in both allopurinol groups. In groups with moderate renal impairment the primary endpoint was achieved by 44% receiving febuxostat 80 mg, 45% receiving 120 mg, and 60% receiving 240 mg, compared with 0% in the allopurinol and placebo groups [Schumacher et al. 2008].
In the CONFIRMS trial the main objective was to compare the urate-lowering efficacy of febuxostat at doses of 40 and 80 mg compared with allopurinol 300/200 mg in patients with mild-to-moderate renal impairment, and also to obtain prospective and uniform information regarding the safety of febuxostat, especially regarding cardiovascular safety. A total of 2269 patients were randomized to febuxostat 40 mg or 80 mg and allopurinol 300 mg or 200 mg in moderate renal impairment to compare urate-lowering efficacy and safety in subjects with gout and sUA greater than 8.0 mg/dl in a 6-month trial [Becker et al. 2010].
The primary endpoint was the proportion of all patients and those with mild/moderate renal impairment achieving sUA less than 6.0 mg/dl. Safety assessments included a blinded adjudication of each cardiovascular adverse event and death using the Anti-Platelet Trialists' Collaboration (APTC) endpoints. The primary endpoint was achieved in 45%, 67% and 42% of patients on febuxostat 40 mg, 80 mg and allopurinol, respectively. No statistical difference was seen between febuxostat 40 mg and allopurinol and it was considered as noninferior to allopurinol; however, febuxostat 80 mg was superior to both groups (p < 0.001). In the groups with moderate renal impairment, febuxostat 80 mg was superior (p < 0.001) to both 40 mg and allopurinol (endpoint achieved in 72%, 50%, and 42%, respectively) and febuxostat 40 mg was marginally superior to allopurinol (p < 0.021) [Becker et al. 2010].
Adverse events were not significantly different among groups: APTC rates were 0.0% (95% CI 0.0–0.486) for febuxostat 40 mg and 0.4% (95% CI 0.082–1.155) (three patients) for both febuxostat and allopurinol. One death occurred in each of the febuxostat groups, compared with three deaths in the allopurinol groups [Becker et al. 2010].
The FOCUS trial was a 5-year extension study that assessed reduction and maintenance of sUA levels below 6.0 mg/dl as the primary efficacy endpoint. A total of 116 patients were initially enrolled to receive a dose of 80 mg febuxostat with dose adjustment to either 40 or 120 mg between weeks 4 and 24. At 5 years, 50% of patients were discontinued prematurely from the study with no apparent relation to adverse events; among the remaining 50% of patients, 93% maintained a sUA level below 6.0 mg/dl at 5 years. There was a clear association with no gout flares in these patients and most patients also had tophus resolution [Schumacher et al. 2009].
The EXCEL trial was the other long-term trial that assessed the clinical efficacy and safety of febuxostat against allopurinol. In this study, 1086 patients were enrolled to receive fixed daily doses of febuxostat 80 mg or 120 mg, or allopurinol 300 mg. Dose adjustments were allowed during the first 6 months to maintain sUA levels between 3.0 and 6.0 mg/dl. The primary endpoint, as in most of the trials, was maintenance of sUA below 6.0 mg/dl and other measures assessed were flares requiring treatment, tophus size and safety profile.
After the first month of treatment, nearly 80% of patients receiving either febuxostat dose achieved sUA less than 6 mg/dl, compared with only 46% of subjects on allopurinol. After ULT reassignment, more than 80% of all remaining subjects maintained target levels of sUA at each visit. Maintenance of sUA below 6.0 mg/dl resulted in baseline tophus resolution in 46%, 36%, and 29% of subjects on febuxostat 80 mg, 120 mg and allopurinol, respectively. In addition, gout flares were significantly reduced, obviating the need for gout flare therapy. Overall adverse events did not show significant differences among groups [Becker et al. 2009].
Overall safety in all clinical trials showed that febuxostat was well tolerated. The most common treatment-related adverse effects were headaches, arthralgia, abdominal pain, nausea, mild elevation of liver function tests, and dizziness. In the first trials, cardiovascular events were a concern related to febuxostat treatment, especially concerning thromboembolic events, myocardial infarcts, and strokes [Gray and Walters-Smith, 2011]. However, in the CONFIRMS trial no significant differences were noted among the distinct treatment groups. It appears that cardiovascular events are more related to the known clinical associations of gout and hyperuricemia with hypertension, metabolic syndrome, diabetes, and dyslipidemia than to the initiation of therapy (Table 3).
Febuxostat-treated patients had higher rates of acute gout flares than those treated with allopurinol, and it has been suggested that this is due to the rapid reduction in sUA levels, which induces mobilization of uric acid deposits.
The most common adverse effect leading to discontinuation of febuxostat was elevated liver function tests: in some studies up to 2–3% of patients developed transaminase elevations greater than three times the upper limit of normal. However, these studies did not establish a dose-effect relationship between febuxostat and elevated liver function tests [Reinders and Jansen, 2010].
Compared with other urate-lowering therapeutic agents, febuxostat activity was unaltered in patients with renal impairment, although there are insufficient data assessing patients with a creatinine clearance less than 30 ml/min [Love et al. 2010].
Therapy of gout and hyperuricemia has progressed significantly in the past few years. New therapeutic modalities have been developed that specifically target certain pathogenic mechanisms [Burns and Wortmann, 2011; Dubost et al. 2011; Jansen et al. 2010].
Febuxostat, an orally administered urate-lowering agent, is a new nonpurine xanthine oxidase inhibitor that is more potent than allopurinol at the currently approved dose of 300 mg daily. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment.
In clinical trials, patients treated with febuxostat achieved rapid and substantial reductions in sUA levels. Compared with allopurinol-treated patients, patients receiving febuxostat 80 mg daily were more likely to achieve sUA concentrations less than 6.0 mg/dl. In long-term studies of up to 5 years, febuxostat showed sustained reductions in sUA levels, almost complete elimination of gout flares, and a frequency of adverse events similar to allopurinol.
The most frequently reported adverse events were liver function abnormalities, rash, nausea, and arthralgia. More cardiovascular thromboembolic events occurred in randomized clinical trials in patients treated with febuxostat. A causal relationship between cardiovascular events and febuxostat has, however, not been established, and patients should be monitored for signs and symptoms of myocardial infarction and stroke [Singh, 2010].
The recommended starting dose of febuxostat is 40 mg daily, which may be increased to 80 mg daily after 2 weeks if patients do not achieve sUA levels less than 6.0 mg/dl. Dosage adjustments in the elderly and in patients with mild-to-moderate renal and hepatic insufficiency, and in those taking hydrochlorothiazide, are not required [Grabowski et al. 2010]. Data are lacking, however, on the safety of febuxostat in patients with severe renal insufficiency.
The use of febuxostat and allopurinol in the long-term therapeutic management of hyperuricemia in patients with gout is associated with increased incidence of gout flares. Analysis of gout flare data from the three phase III trials of febuxostat has shown that flare prophylaxis for up to 6 months after the initiation of ULT provides greater benefit than flare prophylaxis for 8 weeks, with no increase in adverse events [Wortmann et al. 2010].
Febuxostat appears to be an appropriate alternative for the treatment of patients with chronic gout and persistent hyperuricemia, and may be indicated in patients with mild-to-moderate renal impairment, those intolerant to allopurinol, or in patients unable to attain sUA levels below 6.0 mg/dl despite adequate therapy with available agents. Febuxostat, however, has not been fully compared with higher doses of allopurinol [Reinders et al. 2009].
Full pharmacoeconomic analyses of febuxostat therapy are lacking, but a recent report from the appraisal committee of the UK National Institute for Health and Clinical Excellence concluded that febuxostat be recommended as an option for the management of chronic hyperuricemia in gout, only for people who are intolerant to allopurinol or for whom allopurinol is contra-indicated [Stevenson and Pandor, 2011].
Evidence suggests that febuxostat is an effective urate-lowering agent with a good safety profile and tolerability. Its efficacy is not affected by age or gender, and it can be safely used in patients with mild-to-moderate renal and hepatic impairment. Long-term, prospective, and controlled studies are required, however, to fully establish its safety profile.
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
L. Espinoza is a member of the speaker's bureau for Takeda Pharmaceuticals.