Download Febuxostat, a novel nonpurine selective inhibitor of xanthine

ARTHRITIS & RHEUMATISM
Vol. 52, No. 3, March 2005, pp 916–923
DOI 10.1002/art.20935
© 2005, American College of Rheumatology
Febuxostat, a Novel Nonpurine Selective Inhibitor of
Xanthine Oxidase
A Twenty-Eight–Day, Multicenter, Phase II, Randomized, Double-Blind,
Placebo-Controlled, Dose-Response Clinical Trial Examining Safety and Efficacy
in Patients With Gout
Michael A. Becker,1 H. Ralph Schumacher, Jr.,2 Robert L. Wortmann,3
Patricia A. MacDonald,4 William A. Palo,4 Denise Eustace,4 Laurent Vernillet,4
and Nancy Joseph-Ridge4
Objective. Gout affects ⬃1–2% of the American
population. Current options for treating hyperuricemia
in chronic gout are limited. The purpose of this study
was to assess the safety and efficacy of febuxostat, a
nonpurine selective inhibitor of xanthine oxidase, in
establishing normal serum urate (sUA) concentrations
in gout patients with hyperuricemia (>8.0 mg/dl).
Methods. We conducted a phase II, randomized,
double-blind, placebo-controlled trial in 153 patients
(ages 23–80 years). Subjects received febuxostat (40 mg,
80 mg, 120 mg) or placebo once daily for 28 days and
colchicine prophylaxis for 14 days prior to and 14 days
after randomization. The primary end point was the
proportion of subjects with sUA levels <6.0 mg/dl on
day 28.
Results. Greater proportions of febuxostattreated patients than placebo-treated patients achieved
an sUA level <6.0 mg/dl at each visit (P < 0.001 for each
comparison). The targeted sUA level was attained on
day 28 in 0% of those taking placebo and in 56% of those
taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg
of febuxostat. The mean sUA reduction from baseline to
day 28 was 2% in the placebo group and 37% in the
40-mg, 44% in the 80-mg, and 59% in the 120-mg
febuxostat groups. Gout flares occurred with similar
frequency in the placebo (37%) and 40-mg febuxostat
(35%) groups and with increased frequency in the
higher dosage febuxostat groups (43% taking 80 mg;
55% taking 120 mg). During colchicine prophylaxis,
gout flares occurred less frequently (8–13%). Incidences
of treatment-related adverse events were similar in the
febuxostat and placebo groups.
Conclusion. Treatment with febuxostat resulted
in a significant reduction of sUA levels at all dosages.
Febuxostat therapy was safe and well tolerated.
Uric acid is the end product of purine degradation in humans. Hyperuricemia, a serum concentration
of urate that exceeds the limit of urate solubility (⬃7.0
mg/dl), is a common biochemical abnormality (1). Aberrations in any of the multiple mechanisms involved in
the production and/or excretion of uric acid may increase serum urate (sUA) concentrations, and persistent
hyperuricemia is a marker of monosodium urate (MSU)
supersaturation in extracellular fluid (2). As such, hyperuricemia is a necessary (but often not sufficient) risk
factor for MSU crystal deposition in tissues, the fundamental pathophysiologic process underlying the clinical
manifestations of gout (3). Gout can thus be defined as
MSU crystal deposition disease.
1
Michael A. Becker, MD: Pritzker School of Medicine, University of Chicago, Chicago, Illinois; 2H. Ralph Schumacher, Jr., MD:
University of Pennsylvania School of Medicine, and Veterans Affairs
Medical Center, Philadelphia, Pennsylvania; 3Robert L. Wortmann,
MD: University of Oklahoma, Tulsa; 4Patricia A. MacDonald, BSN,
NP, William A. Palo, MS, Denise Eustace, BA, Laurent Vernillet,
PhD, Nancy Joseph-Ridge, MD: TAP Pharmaceutical Products, Inc.,
Lake Forest, Illinois.
Drs. Becker, Schumacher, and Wortmann have received
consulting fees from TAP Pharmaceutical Products.
Address correspondence and reprint requests to Michael A.
Becker, MD, 5841 South Maryland Avenue, MC0930, Chicago, IL
60637. E-mail: [email protected].
Submitted for publication June 30, 2004; accepted in revised
form December 13, 2004.
916
FEBUXOSTAT IN PATIENTS WITH GOUT
Under conditions of persistent urate crystal deposition, gout may progress from episodic attacks of acute
inflammatory arthritis to a disabling chronic disorder
characterized by deforming arthropathy, destructive deposits of urate crystals (tophi) in bones, joints, and other
organs, structural and functional impairment of the
kidney due to interstitial urate crystal deposition, and
urinary tract stones composed entirely or partly of uric
acid crystals (1–3).
Increasing levels of hyperuricemia are paralleled
by increasing incidences of gouty arthritis and uric acid
urolithiasis (4,5), suggesting that long-term management
of gout should address hyperuricemia and urate/uric
acid crystal deposition. Management of gout requires
long-term treatment aimed at lowering sUA levels to a
subsaturating range (usually, ⬍6.0 mg/dl) at which urate
crystal formation and deposition are prevented or reversed. Treatment of gout, although frequently successful, remains largely based on decades-old observational
studies rather than on randomized controlled trials or
validated clinical guidelines (6,7).
During the initiation of treatment with antihyperuricemic agents, gout flares may occur. In one study, the
incidence of gout flares was 40% within the first month
and 27% within the second month, with fewer attacks
(6–11%) noted during the following 3–6 months (8).
Prophylaxis with colchicine or nonsteroidal antiinflammatory drugs has thus been recommended. Despite the
frequency of acute flares of gout early in treatment,
several benefits in long-term outcomes have been attributed to persistent maintenance of the sUA level below
the solubility limit (1,2,9–14). These include reduced
frequencies of acute gouty attacks and uric acid urolithiasis and decreased prevalence of chronic gouty arthropathy and tophaceous gout (9–14).
Febuxostat (2-[3-cyano-4-isobutoxyphenyl]-4methylthiazole-5-carboxylic acid) is an orally administered nonpurine selective inhibitor of xanthine oxidase
(XO), the enzyme that catalyzes the synthesis of uric
acid from hypoxanthine and xanthine (15). In vitro
studies have shown that febuxostat is a potent ligand for,
and inhibitor of, both the oxidized and reduced forms of
XO (15–17). In contrast, allopurinol, a purine analog,
weakly inhibits only the oxidized form of XO (2), and its
oxidized derivative, oxypurinol, binds only to the reduced form of XO. Although oxypurinol binds to XO
with high affinity and is a potent inhibitor, the binding
and inhibition are reversed over several hours as a result
of auto-oxidation of the molybdenum-pterin moiety of
the enzyme. Indeed, in animal studies, febuxostat has
shown more potent and longer-lasting hypouricemic
917
activity than allopurinol (17–19). Previous clinical studies have also shown that febuxostat produces significant
dose-dependent decreases in sUA levels as a result of
inhibition of uric acid production (20). In addition,
febuxostat has minimal effects on other enzymes of
purine and pyrimidine metabolism (16).
Febuxostat is primarily metabolized by hepatobiliary conjugation, unlike allopurinol and oxypurinol,
which are excreted primarily via the kidneys. A study of
subjects with renal impairment indicated that the serum
urate–lowering effect of febuxostat was unaltered in
patients with mild-to-moderate renal failure (21). To
date, no effect of febuxostat on renal tubular function
has been detected, whereas with allopurinol treatment,
dosage reduction in patients with renal insufficiency is
advised (22). In this study, we assessed the safety and
efficacy of febuxostat in reducing sUA concentrations in
patients with hyperuricemia (ⱖ8.0 mg/dl) and gout.
PATIENTS AND METHODS
Study population. This 28-day, multicenter, phase II,
randomized, double-blind, placebo-controlled, dose-response
clinical trial assessed the safety and efficacy of once-daily oral
febuxostat (40 mg, 80 mg, or 120 mg) in reducing sUA levels in
adult patients with gout and hyperuricemia (sUA ⱖ8.0 mg/dl).
All patients met the American College of Rheumatology
preliminary criteria for the classification of the acute arthritis
of primary gout (23).
Exclusion criteria were as follows: serum creatinine
level ⬎1.5 mg/dl (calculated creatinine clearance ⬍50 ml/
minute); pregnancy or lactation; concurrent therapy with
urate-lowering agents, azathioprine, 6-mercaptopurine, or
medications containing aspirin (⬎325 mg) or other salicylates;
a body mass index ⬎50 kg/m2; a history of xanthinuria, active
liver disease, or hepatic dysfunction; changes in thiazide or
steroid therapy (within 1 month of study) or in hormone
replacement/oral contraceptive therapy (within 3 months of
study); or a history of alcohol abuse or intake of ⱖ14 alcoholcontaining drinks per week.
Study design. The study was conducted at 24 centers in
the US. Institutional Review Board approval was obtained, and
all subjects provided written informed consent. Subjects receiving urate-lowering therapy underwent a 2-week washout period preceding randomization. Colchicine prophylaxis, 0.6 mg
twice daily, was provided during the washout period and the
first 2 weeks of double-blind treatment. Acute flares of gout
occurring after the prophylaxis phase were treated at the
investigator’s discretion.
Weekly visits focused on laboratory testing (purine
metabolism, renal function, and safety monitoring), adverse
events, gouty arthritis flares, concomitant medications, compliance, and changes in physical examination findings or vital
signs. Electrocardiograms (EKGs) and 24-hour urine collections for measurement of uric acid were obtained (without
special dietary preparation) prior to randomization and the
final visit (day 28). Subjects were classified as either underex-
918
BECKER ET AL
compared between each febuxostat group and the placebo
group by Fisher’s exact test. Percentage reductions from
baseline in sUA levels and daily urinary uric acid excretion and
changes from baseline in serum xanthine and hypoxanthine
concentrations were summarized and comparisons were made
using a t-test.
The final efficacy analysis was performed at an adjusted significance level of 0.049, since an administrative
interim analysis was performed at the 0.001 significance level.
All safety analyses were performed at the significance level of
0.05. Statistical tests were 2-sided.
RESULTS
Figure 1. Flow diagram of the enrollment and conduct of the study.
SUA ⫽ serum urate; Cr ⫽ creatinine.
cretors (ⱕ800 mg/24 hours) or overproducers (⬎800 mg/24
hours) of uric acid (3).
Randomization and end points. Of 269 subjects
screened, 153 were randomized to daily febuxostat treatment
at 40 mg (n ⫽ 37), 80 mg (n ⫽ 40), or 120 mg (n ⫽ 38) or to
daily placebo treatment (n ⫽ 38) and received at least 1 dose
of the study drug (Figure 1). Efficacy analyses were based on
an intent-to-treat population (140 subjects with a day –2 sUA
level ⱖ8.0 mg/dl); the additional 13 subjects were excluded
because the baseline sample for measuring sUA was collected
outside the day –2 window. All 153 randomized subjects were,
however, included in analyses of treatment safety and gout
flares.
The primary efficacy end point was the proportion of
subjects in each treatment group with sUA levels ⬍6.0 mg/dl
on day 28. Secondary efficacy end points included the proportion of subjects with sUA levels that had decreased to ⬍6.0
mg/dl on days 7, 14, and 21, the percentage reduction in sUA
from baseline at each visit, and the percentage reduction in
daily urinary uric acid excretion from baseline to day 28. The
incidence of gout flares was determined, and safety assessments included treatment-related adverse events and changes
from baseline in serum concentrations of xanthine and hypoxanthine, laboratory parameters, vital signs, and EKG findings.
Statistical analysis. The proportions of subjects
achieving sUA levels ⬍6.0 mg/dl at each visit were summarized
and comparisons were made using Fisher’s exact test. Additional analyses were performed on the proportions of subjects
achieving sUA levels ⬍4.0 mg/dl and ⬍5.0 mg/dl on day 28.
Adjustments for multiple comparisons for the primary and
secondary efficacy end points were made using Hochberg’s
procedure (24). Subgroup analyses were conducted for the
primary efficacy end point on day 28 for the baseline sUA
level. Incidences of gout flares were summarized by study
period. The incidence of treatment-related adverse events was
Characteristics of the study subjects. The age,
sex, race, baseline sUA level, presence of tophi, and uric
acid production status in the study subjects did not vary
greatly among treatment groups (Table 1). Comorbidities were prevalent in all groups. Nearly one-half of all
randomized subjects had a history of hypertension
(49%) or hyperlipidemia (46%). Obesity (27%), cardiovascular disease (23%), hypercholesterolemia (16%),
and diabetes (13%) were also common. The rate of
discontinuation was similar among the study groups
(3–8%) (Figure 1).
Findings of the efficacy evaluation. Significantly
greater proportions of subjects in each febuxostat group
achieved sUA levels ⬍6.0 mg/dl at each visit, as compared with those in the placebo group (P ⬍ 0.001 for
each comparison) (Figure 2). The majority of subjects in
each febuxostat group attained the targeted sUA concentration as early as day 7, and maintained this targeted
level at subsequent visits. When day 28 sUA values were
analyzed according to the levels at baseline, patients
with the highest baseline sUA levels were less likely to
reach an sUA level ⬍6.0 mg/dl with 40 mg/day of
febuxostat than with either 80 or 120 mg/day (data not
shown). The urate-lowering efficacy was further demonstrated by the significantly greater proportions of
febuxostat-treated patients than placebo-treated patients achieving an sUA level ⬍5.0 mg/dl or ⬍4.0 mg/dl
on day 28 (Figure 3).
The mean percentage reductions in sUA from
baseline levels at each visit (range of mean change
35–59%) were significantly greater in each febuxostat
group than in the placebo group (range of mean change
1.6% increase to 2.2% decrease; P ⬍ 0.001 for each
comparison), with the greatest reductions in the febuxostat group receiving 120 mg/day (range of mean change
53–59%) (data not shown). The mean percentage reductions in daily urinary uric acid excretion from baseline to
day 28 were significantly greater in each febuxostat
FEBUXOSTAT IN PATIENTS WITH GOUT
Table 1.
919
Baseline characteristics of randomized subjects*
Febuxostat
Age, mean ⫾ SD years
% male
% Caucasian
Uric acid production, %†
Underexcretors
Overproducers
Undetermined
Tophus present, %
Comorbidities, %
Cardiovascular disease
Diabetes
Hypercholesterolemia
Hyperlipidemia
Hypertension
Obesity
Baseline serum UA in ITT population
No. of ITT subjects
Serum UA, mean ⫾ SD mg/dl
Placebo
(n ⫽ 38)
40 mg/day
(n ⫽ 37)
80 mg/day
(n ⫽ 40)
120 mg/day
(n ⫽ 38)
52.4 ⫾ 12.6
84
84
52.2 ⫾ 14.0
89
87
55.2 ⫾ 13.1
95
88
56.2 ⫾ 10.8
87
89
79
21
0
24
78
22
0
16
73
23
5
25
79
18
3
29
29
5
8
45
53
26
19
16
16
43
41
14
20
20
20
50
50
40
24
11
18
47
53
29
35
9.87 ⫾ 1.33
34
9.24 ⫾ 0.94
37
9.92 ⫾ 1.30
34
9.58 ⫾ 1.11
* None of the differences in baseline characteristics among treatment groups were statistically significant.
UA ⫽ uric acid; ITT ⫽ intent-to-treat (n ⫽ 140 patients with a serum urate concentration ⱖ8.0 mg/dl on
day ⫺2).
† Based on uric acid measurements in 24-hour urine collections at baseline. Underexcretors had ⱕ800
mg/day of uric acid; overproducers had ⬎800 mg/day of uric acid.
group (range of mean change 44–47%) than in the
placebo group (5.9% increase; P ⬍ 0.001 for each
comparison), and significant percentage reductions between each of the febuxostat groups and the placebo
group were observed regardless of baseline urinary uric
acid production (data not shown).
The overall incidences of flares of gouty arthritis
were similar in the placebo and 40-mg/day febuxostat
groups (37% and 35%, respectively) (Table 2). With
Figure 2. Proportion of the intent-to-treat population (140 patients
with a serum urate concentration ⱖ8.0 mg/dl on day –2) with a serum
urate level ⬍6.0 mg/dl at each study visit, by treatment group.
Figure 3. Proportion of intent-to-treat population (140 patients with a
serum urate concentration ⱖ8.0 mg/dl on day –2) with a serum urate
(sUA) level ⬍5.0 mg/dl or ⬍4.0 mg/dl on day 28, by treatment group.
920
BECKER ET AL
Table 2.
Incidence of gout flares*
Febuxostat
Study period
Placebo
(n ⫽ 38)
40 mg/day
(n ⫽ 37)
80 mg/day
(n ⫽ 40)
120 mg/day
(n ⫽ 38)
Entire study period
Colchicine/study drug cotreatment†
Study drug treatment alone
37
11
34
35
8
30
43
8
40
55
13
42
* Prophylaxis was provided for 14 days before study entry for those washing out of urate-lowering therapy,
and all subjects received 14 days of prophylaxis after randomization. Values are percentages.
† Colchicine was not dispensed to 2 subjects, and 2 other subjects stopped colchicine prior to starting the
febuxostat treatment period.
increasing doses of febuxostat, however, the percentage
of gout flares increased (35%, 43%, and 55% in the
40-mg, 80-mg, and 120-mg febuxostat groups, respectively). The incidences of gout flares when colchicine
was administered with febuxostat or placebo were 8%,
8%, 13%, and 11% for febuxostat 40 mg, 80 mg, and 120
mg and placebo, respectively. When febuxostat or placebo was administered alone, however, gout flare incidences were higher: 30%, 40%, 42%, and 34% for
febuxostat 40 mg, 80 mg, and 120 mg and placebo,
respectively.
Findings of the safety evaluation. Treatment with
febuxostat resulted in significant dose-related increases
in serum hypoxanthine and xanthine concentrations
from baseline to day 28 as compared with placebo
treatment (P ⬍ 0.05 for each comparison) (data not
shown). Serum concentrations of hypoxanthine and xanthine were, however, always substantially below the
solubility limits for these compounds in serum at pH 7.4
(115 mg/dl and 10 mg/dl, respectively) (25). Xanthine
crystals were not observed in urine sediments examined
by light microscopy, x-ray diffraction analysis, and Fourier transform infrared spectroscopic analysis.
There were no significant differences between
the febuxostat and placebo groups in the overall incidence of treatment-related adverse events, with the
majority of events being mild or moderate in severity
Table 3.
(Table 3). Treatment-related abnormalities in liver function test (LFT) results (mild-to-moderate increases in
transaminases, not associated with increases in bilirubin)
were observed in a total of 4 febuxostat-treated subjects
(2 taking 40 mg, 1 taking 80 mg, and 1 taking 120 mg).
These were temporally associated with administration of
colchicine, either alone or with febuxostat. In all instances, LFT values returned to normal limits after
discontinuation of colchicine.
Six patients (1 each in the placebo and 40-mg
febuxostat groups and 2 each in the 80-mg and 120-mg
febuxostat groups) discontinued the study prematurely
because of adverse events, which included diarrhea,
gastrointestinal disorder, abnormal LFT results, delirium tremens, increased creatinine levels, localized angioedema, and suicide attempt. There were no deaths
during the study. Three subjects reported serious adverse events. One subject (taking 80 mg of febuxostat)
developed pneumonia, with delirium tremens due to
alcohol withdrawal. The study medication was discontinued, and 7 days later, the subject developed GuillainBarré syndrome. The investigator considered the pneumonia and delirium tremens unlikely to be related to
febuxostat, while the Guillain-Barré syndrome was considered possibly related. The serious adverse events of
back pain in 1 subject and a suicide attempt in another
subject while receiving 120 mg of febuxostat were re-
Incidence of most frequent treatment-related adverse events*
Febuxostat
Adverse event
Abdominal pain
Diarrhea
Abnormal results of liver
function tests
Placebo
(n ⫽ 38)
40 mg/day
(n ⫽ 37)
80 mg/day
(n ⫽ 40)
120 mg/day
(n ⫽ 38)
5
8
0
3
0
5
3
10
3
3
8
3
* Adverse events reported by at least 2 subjects in any treatment group. Values are percentages.
FEBUXOSTAT IN PATIENTS WITH GOUT
garded as unlikely to be related or not related to drug
administration. There were no other clinically significant
changes in laboratory parameters, vital signs, or EKG
findings.
DISCUSSION
Urate-lowering pharmacotherapy is a keystone in
the management of patients with gout and frequent
attacks of gouty arthritis, chronic gouty arthropathy,
chronic tophaceous gout, renal impairment, or uric acid
urolithiasis (1–3,6,7,9–12,26). The choice of uratelowering agents has been restricted to uricosuric drugs,
which enhance renal uric acid excretion, and the XO
inhibitor allopurinol, which reduces uric acid production
(1–3,6,9,26).
Since the introduction of allopurinol, use of
uricosuric agents has diminished (1,3,9,26), in part because agents such as probenecid have limited efficacy
and/or safety in individuals with renal insufficiency (27)
or prior urolithiasis, and partly because the most potent
uricosuric agent, benzbromarone (28), is unavailable in
the US. Allopurinol is effective in reducing sUA levels,
but achieving normal sUA levels may be difficult in
patients with impaired renal function or in transplant
recipients (2,6,9,26). An uncommon, but significant,
limitation to the use of allopurinol is the risk, more
common in elderly and renally impaired individuals, of
reactions that may include rashes (some severe), hematologic cytopenias, hepatitis, vasculitis, and the potentially life-threatening allopurinol hypersensitivity syndrome (1,9,26,29–34).
This clinical trial demonstrated the dose-related,
prompt, and persistent efficacy of febuxostat in lowering
sUA concentrations in patients with hyperuricemia and
gout. Both the proportions of patients with hyperuricemia who had a reduction in the sUA to clearly subsaturating concentrations (⬍6.0 mg/dl) and the degree of
sUA reduction were significantly greater in all febuxostat treatment groups compared with placebo by day 7,
and these differences were maintained over the 28-day
study period. Consistent with the dose-related differences among the febuxostat-treated groups, patients
with the highest baseline sUA levels were less likely to
achieve an sUA level ⬍6.0 mg/dl with febuxostat at 40
mg/day than with either of the higher dosages, suggesting that therapeutic dosages are likely to fall in the range
of 80–120 mg/day.
Flares of gouty arthritis were common during
treatment with febuxostat or placebo, particularly after
withdrawal of colchicine prophylaxis. Flares occurred
921
more frequently in subjects receiving the higher febuxostat dosages, a finding similar to that reported in
studies of other antihyperuricemic treatments (allopurinol or uricosuric agents) in the absence of colchicine
prophylaxis (1,9,35,36).
This phase II study evaluated the safety profile of
febuxostat in patients with gout but no significant renal
impairment. One potentially important role for febuxostat will be in individuals with concurrent impairment
of renal function. Studies to assess long-term safety in
such individuals are in progress and should supplement
information from a previous 7-day phase I study, which
demonstrated that the serum urate–lowering effect of
febuxostat was unaffected by differences in renal function (21), in contrast to allopurinol, for which dosage
reduction in the presence of renal insufficiency is advised (22).
There were no significant differences between
febuxostat and placebo groups with regard to treatmentrelated adverse events. The majority of events were
mild-to-moderate in severity, and there were no trends
toward dose-relatedness in the febuxostat-treated
groups. Few serious adverse events occurred. No serious
or severe neurologic adverse events were reported, other
than the possibly related Guillain-Barré syndrome in 1
patient.
Febuxostat-associated reductions in sUA levels
and urinary uric acid excretion and increases in serum
concentrations of hypoxanthine and xanthine confirm
prior preclinical and clinical studies supporting XO
inhibition as the primary, and perhaps sole, mechanism
of febuxostat-mediated urate lowering (16,20). In fact,
the kinetic and molecular mechanisms involved in febuxostat inhibition of XO have been delineated and differ
substantially from those accounting for inhibition of this
enzyme by allopurinol (15). Mechanistic differences with
respect to XO inhibition and differences in the metabolism of purine and nonpurine analog inhibitors of XO
may have clinical relevance. That is, allopurinol is closely
related in structure to the purine base hypoxanthine and
participates in a broader range of purine and pyrimidine
metabolic reactions (37–41) than does febuxostat, the
action of which appears to be selective and limited to
XO inhibition (16).
Allopurinol and its major active metabolite oxypurinol are substrates for the enzymes hypoxanthine
guanine phosphoribosyltransferase (37) and orotate
phosphoribosyltransferase (38) and are thereby converted
into the respective allopurinol-5⬘ and oxypurinol-1⬘ and
oxypurinol-7⬘ nucleoside monophosphates. These drug
derivatives, as well as allopurinol ribonucleoside, formed
922
BECKER ET AL
by direct phosphorolysis of allopurinol, have metabolic
consequences that, in humans, include inhibition of
the activities of the enzymes purine nucleoside phosphorylase (39) and orotidylic acid decarboxylase (38),
depletion of intracellular concentrations of phosphoribosylpyrophosphate (37), reduction of rates of purine
nucleotide synthesis de novo (40), and enhanced urinary
excretion of orotidine and orotic acid (41,42). To the
extent that adverse consequences of allopurinol therapy
may relate to actions of this purine analog compound
(or its metabolic products) exclusive of XO inhibition,
the selectivity of febuxostat may lessen the risk for at
least some of the untoward effects of current antihyperuricemic therapy in patients with gout.
We conclude that febuxostat was safe and effective in this brief phase II study. Further clinical studies
aimed at evaluating the long-term safety and clinical efficacy of febuxostat in patients with gout are warranted.
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