Febuxostat for Treatment of Chronic Gout

Charnelda L. Gray, Pharm.D., BCPS; Nafesa E. Walters-Smith, Pharm.D., BCPS

Disclosures

Am J Health Syst Pharm. 2011;68(5):389-398. 

In This Article

Pharmacokinetics

Febuxostat is rapidly absorbed after oral administration, with peak plasma concentrations occurring in 0.5–1.3 hours.[3,29] After multiple oral 40- and 80-mg once-daily doses of febuxostat, the mean ± S.D. maximum plasma drug concentration (Cmax) was 1.6 ± 0.6 μg/mL (n = 30) and 2.6 ± 1.7 μg/mL (n = 227), respectively.[30] The mean terminal elimination half-life (t½) of febuxostat is approximately 5–8 hours. Febuxostat is 99.2% protein bound, primarily to albumin, with an apparent volume of distribution at steady state of 0.7 L/kg.[3,31,32]

Based on a four-week treatment phase in which 10 patients with gout or hyperuricemia or both received febuxostat 20 mg daily, serum uric acid concentrations decreased by 33% (from 8.7 to 5.8 mg/100 mL), with mean ± S.D. maximum and minimum serum uric acid concentrations differing by 0.84 ± 0.34 mg/100 mL for the 24-hour period before administration of the first dose and by 0.96 ± 0.25 mg/100 mL for the 24-hour period after the final administration.[24] There was a steady decrease in the mean serum uric acid levels, which were linearly related to the dosage up to 120 mg per day, at which point the levels plateaued.[3] At dosages exceeding 120 mg per day, the area under the concentration–time curve (AUC) increased with increasing dosages.[29] At steady state, about 1–6% of the orally administered daily dose was excreted into the urine as unchanged drug, and 25–45% of the dose was excreted as total (unchanged plus febuxostat conjugate) drug.[3,30] The acylglucuronide metabolite of febuxostat comprised 22–44% of the dose excreted in the urine due to conjugation by uridine diphosphate glucoronosyl transferase and oxidation via CYP1A2, CYP2C8, and CYP2C9, resulting in 2–8% of the dose excreted in the urine comprising the active metabolites 67M-1, 67M-2, and 67M-4.[29,30] In vitro data showed that febuxostat has a weak inhibitory effect on CYP2D6 and no significant effect on CYP1A2, CYP2C9, CYP2C19, and CYP3A4.[33]

Febuxostat has been evaluated in patients with renal and hepatic dysfunctions, men and women, and the elderly. In one study, febuxostat 80 mg daily was administered orally for seven days to patients with normal renal function (CLcr of >80 mL/min), mild renal impairment (CLcr of 50–80 mL/min), moderate renal impairment (CLcr of 30–49 mL/min), and severe renal impairment (CLcr of 10–29 mL/min).[31] Regression analysis showed that the time to reach peak plasma concentration (tmax) and the Cmax in patients with renal impairment were similar to those in patients with normal renal function, but the AUC and the t½ increased linearly by severity of renal impairment. By day 7, the mean serum uric acid concentrations decreased by 55–64%, regardless of renal function. The authors suggested that conjugated febuxostat underwent enterohepatic cycling and increased biliary excretion, resulting in a lower renal clearance and higher AUC and t½ without affecting the overall decrease in serum uric acid. Thus, the 80-mg dose of febuxostat did not appear to require adjustment based on renal function.[31]

The effect of hepatic impairment was assessed in three groups of individuals with normal hepatic function, mild hepatic impairment (Child-Pugh class A), and moderate hepatic impairment (Child-Pugh class B) who were given febuxostat 80 mg daily for seven consecutive days.[32] No statistically significant differences in the Cmax of unbound febuxostat, tmax, t½, and AUC for unbound febuxostat and metabolites 67M-1, 67M-2, and 67M-4 were demonstrated when the mild and moderate hepatic impairment groups were compared with the group with normal hepatic function.[32] After giving febuxostat 80 mg daily, the change in serum uric acid concentrations from baseline was statistically but not clinically significant (p ≤ 0.05) for each group, with decreases of 62.5% (from 4.77 to 1.83 mg/dL) in the normal hepatic function group, 48.9% (from 4.95 to 2.66 mg/dL) in the mild hepatic impairment group, and 47.8% (from 5.45 to 2.85 mg/dL) in the moderate impairment group. A decrease in biliary clearance of uric acid in patients with mild or moderate hepatic impairment may be the result of xanthine, febuxostat, or febuxostat metabolites using the same biliary transport system, which is more easily saturable in patients with hepatic impairment. Khosravan et al.[32] concluded that no dosage adjustment is necessary in patients with mild-to-moderate hepatic impairment, as there is increased renal excretion and decreased biliary excretion of uric acid with febuxostat.

To determine the effect of age and sex on febuxostat pharmacokinetic and pharmacodynamic parameters, Khosravan and colleagues[14] studied 48 patients, divided into four groups of 12: men age 18–40 years, women age 18–40 years, men age 65 years or older, and women age 65 years or older. Each person was given febuxostat 80 mg once daily for seven days. The Cmax was 31.5 ng/mL in women and 23.6 ng/mL in men (p ≤ 0.01), and the AUC was 62.8 ng · hr/mL in women and 53.9 ng · hr/mL in men (p ≤ 0.05); when body weight at baseline was analyzed as a covariate, these parameters were no longer statistically significant.[14] In women, the percentage decrease in the 24-hour mean serum uric acid concentration was 59% versus 52% in men (p ≤ 0.01), but this was not clinically significant. There were no statistically significant differences between the younger age groups and those 65 years or older in regard to serum uric acid, AUC, and Cmax for febuxostat and its metabolites 67M-1, 67M-2, and 67M-4.[14] Dosage adjustments were not necessary based on age or sex.

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