Furic Mechanism of Action

Pharmacology: Pharmacodynamics: Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, febuxostat resulted in a dose dependent decrease in 24-hr mean serum uric acid concentrations and an increase in 24-hr 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-hr mean serum uric acid concentrations was between 40-55% 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.
Mechanism of Action: Febuxostat, a xanthine oxidase (XO) 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.
Pharmacokinetics: In healthy subjects, maximum plasma concentrations (C_max) and area under the concentration-time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10-120 mg. There is no accumulation when therapeutic doses are administered every 24 hrs. Febuxostat has an apparent mean terminal elimination half-life (t_½) of approximately 5-8 hrs. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analysis 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 (C_max) of febuxostat occured between 1-1.5 hrs post-dose. After multiple oral 40 mg and 80 mg once daily doses, C_max 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.
Distribution: The mean apparent steady-state volume of distribution (V_ss/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 and oxidation via cytochrome P450 (CYP450) enzymes including CYP1A2, 2CB 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 formulation of 4 pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat.
Elimination: Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of C-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%). The apparent mean terminal elimination t_½ of febuxostat was approximately 5-8 hrs.
Special Populations: Pediatric Use: The pharmacokinetics of febuxostat in patients under the age of 18 years have not been studied.
Renal Impairment: Following multiple 80 mg doses of febuxostat in healthy subjects with mild [creatinine clearance (CrCl) 50-80 mL/min], moderate (CrCl 30-49 mL/min) or severe renal impairment (CrCl 10-29 mL/min), the C_max of febuxostat did not change relative to subjects with normal renal function (CrCl >80 mL/min). Area under the concentration-time curve (AUC) and t_½ of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among 3 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 C_max and AUC values for 3 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 serum uric acid <6 mg/dL after 2 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 doses of febuxostat 80 mg in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20-30% increased was observed for both C_max and AUC₂₄ (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.