Febuxostat

Febo
Uloric
Introduction:
Gout affects a large number of individuals worldwide and continues to
increase in incidence. Gout includes a group of disorders including
painful attacks of acute, monarticular, inflammatory arthritis due to uric
acid crystals, deposition of urate crystals in joints, deposition of urate
crystals in renal parenchyma, urolithiasis (formation of calculus in the
urinary tract), and nephrolithiasis (formation of kidney stones).
The underlying metabolic aberration in gout is hyperuricemia.
Hyperuricemia is associated with a serum uric acid (sUA) level of 6.8
mg/dL or greater, which is the upper limit of solubility of uric acid in
extracellular fluids. However, hyperuricemia also has been associated
with other levels of serum uric acid depending on factors such as gender
and age, for example, hyperuricemia leads to gout when urate crystals
are formed from supersaturated body fluids and deposited in joints,
tophi, and parenchymal organs. In addition to gout, other disorders
related to elevated serum uric acid levels include gout-associated
inflammation, kidney stones, renal disorders, cardiovascular diseases,
aberrant metabolic conditions, fatty liver disease, cognitive impairment,
and dementia
• Methods for treating gout include the use of uric acid synthesis
inhibitors to inhibit the accumulation of uric acid in the body. For
example, use of xanthine oxidase inhibitors, such as febuxostat and
allopurinol. Febuxostat is a nonpurine selective inhibitor of xanthine
oxidase that works by non-competitively blocking the channel leading
to the active site on xanthine oxidase. Xanthine oxidase is needed to
successively oxidize both hypoxanthine and xanthine to uric acid.
Febuxostat inhibits xanthine oxidase, thereby reducing production
of uric acid.
• For treatment of hyperuricemia in patients with gout, febuxostat is
recommended at 40 mg or 80 mg once daily. No dose adjustment is
necessary when administering febuxostat in patients with mild to
moderate renal and hepatic impairment.
• Febuxostat is commercially available under the brand name
Uloric® by Takeda in two strengths, 40 mg and 80 mg, in the form
of film-coated tablets. The therapeutic dose required to be
administered must thus be increased in order to compensate for
this disadvantage.
• The chemical name of febuxostat is 2-(3-cyano-4-isobutyloxyphenyl)-
4-methyl-5-thiazolecarboxylic acid. It is disclosed in U.S. Patent No.
5,614,520. Febuxostat has the following chemical structure:
Pharmacology:
Mechanism of Action
• Febuxostat, a xanthine oxidase inhibitor, achieves its therapeutic effect
by decreasing serum uric acid. Febuxostat is not expected to inhibit
other enzymes involved in purine and pyrimidine synthesis and
metabolism at therapeutic concentrations.
Pharmacology:
Pharmacodynamics
Effect on Uric Acid and Xanthine Concentrations In healthy patients,
Febuxostat resulted in a dose dependent decrease in 24 hour mean
serum uric acid concentrations and an increase in 24 hour mean serum
xanthine concentrations. In addition, there was a decrease in the total
daily urinary uric acid excretion. Also, there was an increase in total
daily urinary xanthine excretion. Percent reduction in 24 hour mean
serum uric acid concentrations was between 40% and 55% at the
exposure levels of 40 mg and 80 mg daily doses.
Effect on Cardiac Repolarization The effect of ULORIC on cardiac
repolarization as assessed by the QTc interval was evaluated in normal
healthy patients and in patients with gout. ULORIC in doses up to 300
mg daily, at steady-state, did not demonstrate an effect on the QTc
interval.
Pharmacology:
Pharmacokinetics
• Absorption: The absorption of radiolabeled febuxostat following oral dose
administration was estimated to be at least 49% (based on total radioactivity
recovered in urine). Maximum plasma concentrations of febuxostat occurred
between 1 and 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily
doses, Cmax is approximately 1.6 ± 0.6 mcg/mL (N=30), and 2.6 ± 1.7 mcg/mL
(N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been
studied. Following multiple 80 mg once daily doses with a high fat meal, there was a
49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no
clinically significant change in the percent decrease in serum uric acid concentration
was observed (58% fed vs. 51% fasting). Thus, Febuxostat may be taken without
regard to food. Concomitant ingestion of an antacid containing magnesium
hydroxide and aluminum hydroxide with an 80 mg single dose of Febuxostat has
been shown to delay absorption of febuxostat (approximately one hour) and to cause
a 31% decrease in Cmax and a 15% decrease in AUC∞. As AUC rather than Cmax
was related to drug effect, change observed in AUC was not considered clinically
significant. Therefore, Febuxostat may be taken without regard to antacid use.
Pharmacology:
Elimination
• Febuxostat is eliminated by both hepatic and renal pathways.
Following an 80 mg oral dose of 14Clabeled febuxostat,
approximately 49% of the dose was recovered in the urine as
unchanged febuxostat (3%), the acyl glucuronide of the drug (30%),
its known oxidative metabolites and their conjugates (13%), and other
unknown metabolites (3%). In addition to the urinary excretion,
approximately 45% of the dose was recovered in the feces as the
unchanged febuxostat (12%), the acyl glucuronide of the drug (1%),
its known oxidative metabolites and their conjugates (25%), and other
unknown metabolites (7%). The apparent mean terminal elimination
half-life (t1/2) of febuxostat was approximately 5 to 8 hours.
CLINICAL STUDIES
Study 1
• randomized patients to: ULORIC 40 mg daily, ULORIC 80 mg daily,
or allopurinol (300 mg daily for patients with estimated creatinine
clearance (Clcr) ≥60 mL/min or 200 mg daily for patients with
estimated Clcr ≥30 mL/min and ≤59 mL/min). The duration of Study 1
was six months.
Study 2
• randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120
mg daily, ULORIC 240 mg daily or allopurinol (300 mg daily for
patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg daily
for patients with a baseline serum creatinine greater than 1.5 mg/dL
and ≤2 mg/dL). The duration of Study 2 was six months.
Study 3
• a 1 year study, randomized patients to: ULORIC 80 mg daily,
ULORIC 120 mg daily, or allopurinol 300 mg daily. Patients who
completed Study 2 and Study 3 were eligible to enroll in a Phase 3
long-term extension study in which patients received treatment with
ULORIC for over three years.
Serum Uric Acid Level less than 6 mg/dL at
Final Visit
• ULORIC 80 mg was superior to allopurinol in lowering serum uric
acid to less than 6 mg/dL at the final visit. ULORIC 40 mg daily,
although not superior to allopurinol, was effective in lowering serum
uric acid to less than 6 mg/dL at the final visit (Table 3).