Fexoxan Mechanism of Action

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.
Pharmacodynamics: 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 and 80 mg daily doses.
Effect on Cardiac Repolarization: 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.
Clinical Studies: 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.
Pharmacokinetics: 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.
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.
Distribution: 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 and 80 mg doses.
Metabolism: Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, 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.
Elimination: Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg 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 (7%).
The apparent mean terminal elimination half-life (t1/2) of febuxostat was approximately 5 to 8 hours.
Special populations: 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 patients. No dose adjustment is necessary in geriatric patients (see Precautions).
Renal Impairment: In a dedicated phase 1 pharmacokinetics study, following multiple 80 mg doses of FEBUXOSTAT in healthy patients with mild (Clcr 50 to 80 mL/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 patients with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in patients with renal impairment in comparison to patients 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 2-4-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).
Based on population pharmacokinetics analysis, following 40 mg or 80 mg doses of FEBUXOSTAT, the mean oral clearance (CL/F) values of febuxostat in patients with gout and mild (n=334), moderate (n=232) or severe (n=34) renal impairment were decreased by 14%, 34%, and 48%, respectively, compared to patients with normal (n=89) renal function. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were decreased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function.
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 and AUC24 (total and unbound) in hepatic impairment groups compared to patients 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 and AUC24 of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC24 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.
Drug-Drug Interactions: 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 (see Contraindications and Interactions).
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, 2C219, 2D6, or 3A4 and it also does not induces one particular enzyme isoforms 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 (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%).
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 patients. 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).
Non-Clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of the urinary bladder was observed at 24 mg/kg (25 times the MHRD on an AUC basis) and 18.7 mg/kg (12.5 times the MHRD on an AUC basis) in male rats and female mice, respectively. The urinary bladder neoplasm were secondary to calculus formation in the kidney and urinary bladder.
Febuxostat showed a positive clastogenic response in chromosomal aberration assays in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro chromosomal aberration assay in human peripheral lymphocytes, the L5178Y mouse lymphoma cell line assay, basis in vivo mouse micronucleus assay, and the rat unscheduled DNA synthesis assay.
Fertility and reproductive performance were unaffected in male or female rats that received febuxostat at oral doses up to 48 mg/kg/day (approximately 31 to 40 times the MHRD on an AUC basis in males and females respectively).
Animal Toxicology: A 12 month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately 4 times the MHRD on an AUC basis). As similar effects of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg/kg (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).