Febsan 40/Febsan 80 Mechanism of Action

Pharmacology: Febuxostat, a xanthine oxidase (XO) inhibitor, achieves its therapeutic effect by decreasing serum uric acid (sUA). Febuxostat is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.
Pharmacokinetics: In healthy subjects, the 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 the therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t½) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricaemia 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 the urine).
Maximum plasma concentrations of febuxostat occurred between 1 to 1.5 hours postdose.
After multiple oral 40 mg and 80 mg once daily doses, the 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 the Cmax and 18% decrease in the AUC, respectively. However, no clinically significant change in the percent decrease in the sUA concentration was observed (58% fed versus 51% fasting). Thus, febuxostat may be taken without regard to food.
Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide with an 80 mg single dose of febuxostat has been shown to delay absorption of febuxostat (approximately 1 hours) and to cause a 31% decrease in Cmax and a 15% decrease in the AUC∞. As the AUC rather than the Cmax was related to the drug effect, the change observed in the 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 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 the plasma of humans at a much lower extent than febuxostat.
In the urine and the faeces, 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 the 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 metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the faeces as 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 t½ of febuxostat was approximately 5 to 8 hours.