Pharmacology: Pharmacodynamics: Mechanism of Action:
Febuxostat is a xanthine oxidase inhibitor. The active ingredient in Febuxostat T is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16
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.
Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, 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 daily dose.
Effect on Cardiac Rapolarization: The effect of Febuxostat on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. Febuxostat in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval.
A serum uric acid level of less than 6 mg/dL is the goal of anti-hyperuricemic therapy and has been established as appropriate for the treatment of gout.
Management of Hyperuricemia in Gout: The efficacy of Febuxostat was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as a baseline serum uric acid level ≥8 mg/dL.
Study 1 randomized patients to: Febuxostat 40 mg daily, Febuxostat 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 ≥30mL/min and ≤59 mL/min). The duration of Study 1 was six months.
Study 2 randomized patients to: placebo, Febuxostat 80 mg daily, Febuxostat 120 mg daily, Febuxostat 240 mg daily or allopurinol (300 mg daily for patients with a baseline serum creatinine ≤1.5 mg/dL or 100mg 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: Febuxostat 80 mg daily, Febuxostat 120 mg daily, or allopurinol 300 mg daily. Subjects who completed Study 2 and Study 3 were eligible to enroll in a phase 3 long-term extension study in which subjects received treatment with Febuxostat for over three years.
In all three studies, subjects received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1 the duration of prophylaxis was eight weeks.
The efficacy of Febuxostat was also evaluated in a four-week dose ranging study which randomized patients to: placebo, Febuxostat 40 mg daily, Febuxostat 80 mg daily, or Febuxostat 120 mg daily. Subjects who completed this study were eligible to enroll in a long-term extension study in which subjects received treatment with Febuxostat for up to five years.
Patients in these studies were representative of the patient population for which Febuxostat use is intended. Table 1 summarizes the demographics and baseline characteristics for the subjects enrolled in the studies. (See Study 1.)
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Serum Uric Acid Level less than 6 mg/dL at Final Visit: Febuxostat 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg/dL at the final visit. Febuxostat 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 2).
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In 76% of Febuxostat 80 mg patients, reduction in serum uric acid levels to less than 6 mg/dL was noted by the Week 2 visit. Average serum uric acid levels were maintained at 6 mg/dL or below throughout treatment in 83% of these patients.
In all treatment groups, fewer subjects with higher baseline serum urate levels ≥10 mg/dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg/dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg/dL with Febuxostat 80 mg than with Febuxostat 40 mg or allopurinol.
Study 1 evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL/min). The results in this sub-group of patients are shown in Table 3. (See Table 3.)
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In healthy subjects, maximum plasma concentrations (Cmax
) and AUC of Febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy subjects.
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 80mg 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.
The mean apparent steady state volume of distribution (Vss/F) of Febuxostat was approximately 50 L (CV~40%). The plasma protein binding of Febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg doses.
Febuxostat is extensively metabolized by both conjugation via uridine diphosphateglucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of Febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than Febuxostat. In urine and feces, acyl glucuronide metabolites of Febuxostat (35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of Febuxostat in vivo.
Febuxostat is eliminated by both hepatic and renal pathways. The apparent mean terminal elimination half-life (t1/2) of Febuxostat was approximately 5 to 8 hours. Following an 80mg oral dose of 14C-labeled 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%).
Pediatric Use: The pharmacokinetics of Febuxostat in patients under the age of 18 years have not been studied.
Geriatric Use: The Cmax
and AUC of febuxostat and its metabolites following multiple oral doses of Febuxostat in geriatric subjects (≥65 years) were similar to those in younger subjects (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger subjects. No dose adjustment is necessary in geriatric patients.
Renal Impairment: Following multiple 80 mg doses of Febuxostat in healthy subjects with mild (Clcr 50 to 80mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax
of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax
and AUC values for three active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).
No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended starting dose of Febuxostat is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/mL after two weeks with 40 mg, Febuxostat 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients.
Febuxostat has not been studied in end stage renal impairment patients who are on dialysis.
Hepatic Impairment: Following multiple 80 mg doses of Febuxostat in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax
(total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients.
Gender: Following multiple oral doses of Febuxostat, the Cmax
of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax
and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender.
Race: No specific pharmacokinetic study was conducted to investigate the effects of race.
Effect of Febuxostat on Other Drugs: Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine, and Theophylline: Febuxostat is an XO inhibitor. A drug-drug interaction study evaluating the effect of Febuxostat upon the pharmacokinetics of theophylline (an XO substrate) in healthy subjects showed that coadministration of febuxostat with theophylline resulted in an approximately 400-fold increase in the amount of 1-methylxanthine, one of the major metabolites of theophylline, excreted in the urine. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline.
Drug interaction studies of Febuxostat with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by Febuxostat may cause increased plasma concentrations of these drugs leading to toxicity. Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine.
Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Although Febuxostat drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because Febuxostat is a xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or mercaptopurine that could result in severe toxicity.
P450 Substrate Drugs: In vitro
studies have shown that Febuxostat does not inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6, or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3M at clinically relevant concentrations. As such, pharmacokinetic interactions between Febuxostat and drugs metabolized by these CYP enzymes are unlikely.
Effect of Other Drugs on Febuxostat: Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between Febuxostat and a drug that inhibits or induces one particular enzyme isoform is in general not expected.
In Vivo Drug Interaction Studies:
Theophylline: No dose adjustment is necessary for theophylline when coadministered with Febuxostat. Administration of Febuxostat (80 mg once daily) with theophylline resulted in an increase of 6% in Cmax
and 6.5% in AUC of theophylline. These changes were not considered statistically significant. However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as a result of XO inhibition by Febuxostat. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister Febuxostat and theophylline.
Colchicine: No dose adjustment is necessary for either Febuxostat or colchicine when the two drugs are coadministered. Administration of Febuxostat (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in Cmax
and 7% in AUC24
of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with Febuxostat (120 mg daily) resulted in a less than 11% change in Cmax
or AUC of colchicine for both AM and PM doses. These changes were not considered clinically significant.
Naproxen: No dose adjustment is necessary for Febuxostat or naproxen when the two drugs are coadministered. Administration of Febuxostat (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in Cmax
and a 40% increase in AUC of febuxostat. The increases were not considered clinically significant. In addition, there were no significant changes in the Cmax
or AUC of naproxen (less than 2%).
Indomethacin: No dose adjustment is necessary for either Febuxostat or indomethacin when these two drugs are coadministered. Administration of Febuxostat (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in Cmax
or AUC of febuxostat or indomethacin (less than 7%).
Hydrochlorothiazide: No dose adjustment is necessary for Febuxostat when coadministered with hydrochlorothiazide. Administration of Febuxostat (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in Cmax
or AUC of febuxostat (less than 4%), and serum uric acid concentrations were not substantially affected.
Warfarin: No dose adjustment is necessary for warfarin when coadministered with Febuxostat. Administration of Febuxostat (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the coadministration of Febuxostat.
Desipramine: Coadministration of drugs that are CYP2D6 substrates (such as desipramine) with Febuxostat are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro
and in vivo
. Administration of Febuxostat (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax
(16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC).