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Pharmacology: Pharmacodynamics: Febuxostat (Urica) is a xanthine oxidase inhibitor that achieve its therapeutic effect by decreasing serum uric acid Febuxostat (Urica) is not expected to inhibit other enzymes involved in purine pyrimidine synthesis and metabolism at therapeutic concentrations.
In healthy subjects Febuxostat (Urica) resulted in dose dependent decreased in 24-hrs mean serum uric acid concentrations and an increase in 24-hrs mean serum xanthine concentrations There was also decrease in total urinary uric acid excretion and an increase in total daily urinary xanthine excretion. Percent reduction in 24-hrs mean serum uric acid concentrations was between 40-55% at the exposure levels of 40 mg and 80 mg daily doses
Pharmacokinetics: Maximum plasma concentrations (Cmax) and area under the curve (AUC) of Febuxostat (Urica) increased in a dose proportional manner following single and multiple dose of 10-120 mg in healthy subjects. There is no accumulation when therapeutic doses are administered every 24 hrs. Febuxostat (Urica) has an apparent mean terminal elimination half-life (t1/2) of approximately 5-8 hrs. The pharmacokinetic parameters of Febuxostat (Urica) for patients with hyperuricemia and gout were similar to those estimated in healthy subjects.
The absorption radiolabeled Febuxostat (Urica) following oral dose administration was estimated to be at least 49% with maximum plasma concentration occurring between 1-1.5 hrs post-dose. After multiple oral 40 mg and 80 mg once daily doses. Cmax is approximately 1.6±0.6 mcg/mL, and 2.6±1.7 mcg/mL, respectively. The absolute bioavailability of Febuxostat (Urica) 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.
Concomitant ingestion of an antacid-containing magnesium hydroxide and aluminum hydroxide with an 80-mg single dose of Febuxostat (Urica) has been shown to delay absorption of Febuxostat (Urica) (approximately 1 hr) and to cause a 31% decrease in Cmax and a 15% increase in AUC infinity. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant.
The mean apparent steady state volume of distribution (Vss/F) of Febuxostat (Urica) was approximately 50 L. The plasma protein binding of Febuxostat (Urica) is approximately 99.2%, primarily to albumin and is constant over the concentration range achieved with 40-mg and 80-mg doses.
Febuxostat (Urica) is extensively metabolized by both conjugation via uridine diphosphate glucuronyl transferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9 & UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 & 2C9 and non-P450 enzymes. The oxidation of the isobutyl side chain leads to the formation of 4 pharmacologically active hydroxy metabolites, all of which occur in human plasma at a much lower extent than Febuxostat (Urica).
The apparent mean terminal elimination (t1/2) of Febuxostat (Urica) is approximately 5-8 hrs.
In urine and faeces, acyl glucuronide metabolites of Febuxostat (Urica) and oxidative metabolites 67M-1, 67M-2, and 67M-4, a secondary metabolite from 67-M-1, appeared to be the major metabolites of Febuxostat (Urica) in vivo.
Febuxostat (Urica) is eliminated by both hepatic and renal pathways. Following an 80-mg oral dose of 14C-labeled Febuxostat (Urica), approximately 49% of the dose was recovered in the urine as unchanged Febuxostat (Urica) (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%) and other known metabolites (3%). Also, approximately 45% of the dose was recovered in feces as unchanged Febuxostat (Urica) (12%). The acyl glucuronide (1%), its known oxidative metabolites and their conjugates (25%) and other known metabolites (7%).
