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Pharmacology: Pharmacodynamics: 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 previously mentioned 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.
Pharmacokinetics: Absorption: Maximum plasma concentrations of Febuxostat occurred between 1 to 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 ± 0.6 mcg per mL, and 2.6 ± 1.7 mcg per mL, respectively.
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. Thus, it may be taken without regard to food.
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 conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system.
Elimination: Febuxostat is eliminated by both hepatic and renal pathways. The apparent mean terminal elimination half-life (1/2) of Febuxostat was approximately 5 to 8 hours.
Special Populations: Renal impairment: Following multiple doses of 80 mg of febuxostat in patients with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe renal impairment (Clcr 10-29 mL per min), the Cmax of Febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL per min). However, no dose adjustment is necessary in patients with mild to moderate renal impairment.
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, an average of 20-30% increase was observed for both Cmax and AUC (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. 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.
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.
Gender: Following multiple oral doses of febuxostat the Cmax and AUC were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In, addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is needed based on gender.
Toxicology: Preclinical safety data: Effects in non-clinical studies were generally observed at exposures in excess of the maximum human exposure.
Carcinogenesis: Two-year carcinogenicity studies were conducted in rats and mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg per kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg per day) and 18.75 mg per kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.
Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells.
Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day (approximately 35 times the human plasma exposure at 80 mg per day) had no effect on fertility and reproductive performance of male and female rats. A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for Febuxostat.
