Pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production, ATC code: M04AA03
Mechanism of action
Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine → xanthine → uric acid. Both steps in the above transformations are catalyzed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. Febuxostat has been shown to potently inhibit both the oxidized and reduced forms of XO. At therapeutic concentrations Febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.
In healthy subjects, maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of Febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. For doses between 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed for Febuxostat. There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours.
Population pharmacokinetic/pharmacodynamic analyses were conducted in 211 patients with hyperuricaemia and gout, treated with UNSIATEM 40-240 mg QD. In general, Febuxostat pharmacokinetic parameters estimated by these analyses are consistent with those obtained from healthy subjects, indicating that healthy subjects are representative for pharmacokinetic/pharmacodynamic assessment in the patient population with gout.
Febuxostat is rapidly (tmax of 1.0-1.5 h) and well absorbed (at least 84%). After single or multiple oral 80 and 120 mg once daily doses, Cmax is approximately 2.8-3.2 µg/mL, and 5.0-5.3 µg/mL, respectively. Absolute bioavailability of the Febuxostat tablet formulation has not been studied.
Following multiple oral 80 mg once daily doses or a single 120 mg dose with a high fat meal, there was a 49% and 38% decrease in Cmax and a 18% and 16% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed where tested (80 mg multiple dose). Thus, UNSIATEM may be taken without regard to food.
The apparent steady state volume of distribution (Vss/F) of Febuxostat ranges from 29 to 75 L after oral doses of 10-300 mg. The plasma protein binding of Febuxostat is approximately 99.2%, (primarily to albumin), and is constant over the concentration range achieved with 80 and 120 mg doses. Plasma protein binding of the active metabolites ranges from about 82% to 91%.
Febuxostat is extensively metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system. Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans. In vitro studies with human liver microsomes showed that those oxidative metabolites were formed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and Febuxostat glucuronide was formed mainly by UGT 1A1, 1A8, and 1A9.
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 active substance (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 faeces as the unchanged Febuxostat (12%), the acyl glucuronide of the active substance (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).
Once daily without regard to food. If serum uric acid is > 6 mg/dL (357 µmol/L) after 2-4 weeks.
UNSIATEM works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks. The therapeutic target is to decrease and maintain serum uric acid below 6 mg/dL (357μmol/L).
Gout flare prophylaxis of at least 6 months is recommended