RiteMED Febuxostat Mechanism of Action

Antigout Preparation.
Pharmacology: Pharmacodynamics: 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 previously mentioned transformations are catalyzed by xanthine oxidase. FEBUXOSTAT is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting xanthine oxidase. FEBUXOSTAT is a potent, non-purine selective inhibitor of xanthine oxidase (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 xanthine oxidase. 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.
Pharmacokinetics: Absorption: FEBUXOSTAT is rapidly (t_max of 1.0-1.5 h) and well absorbed (at least 84%). After single or multiple oral 80 and 120 mg once daily doses, C_max 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 C_max and an 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, FEBUXOSTAT may be taken without regard to food.
Distribution: The apparent steady state volume of distribution (V_ss/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%.
Metabolism: 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.
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 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 feces as the unchanged FEBUXOSTAT (12%), the acyl glucuronide of the active substance (1%) its known oxidative metabolites and its conjugates (25%) and other unknown metabolites (7%).
FEBUXOSTAT has an apparent mean terminal elimination half-life (t_1/2) of approximately 5 to 8 hours.
Patients with renal impairment: Following multiple doses of 80 mg of FEBUXOSTAT in patients with mild, moderate or severe renal insufficiency, the C_max of FEBUXOSTAT did not change, relative to subjects with normal renal function. The mean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 μg.h/mL in the normal renal function group 13.2 μg.h/mL in the severe renal dysfunction group. The C_max and AUC of active metabolites increased up to 2- and 4-fold, respectively. However, no dose adjustment is necessary in patients with mild or moderate renal impairment.
Patients with hepatic impairment: Following multiple doses of 80 mg of FEBUXOSTAT in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, the C_max and AUC of FEBUXOSTAT and its metabolites did not change significantly compared to subjects with normal hepatic function. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).
Age: There were no significant changes observed in AUC of FEBUXOSTAT or its metabolites following multiple oral doses of FEBUXOSTAT in elderly as compared to younger healthy subjects.