Febuxostat in the management of hyperuricemia and chronic gout: a review

Figures & data

Table 1 Pharmacokinetics of febuxostat

Reference	Subjects	Dose	Results
(Becker et al 2004a; Khosravan et al 2006b)	Male and female healthy volunteers (n = 142)	Different doses (10, 20, 30, 40, 50, 70, 90, 120, 160, 180, and 240 mg) with 12 subjects each group for 2 weeks	A linear PK and dose-response (% decrease in sUA) relationship for febuxostat dosages within the 10–120 mg range
(Komoriya et al 2004)	Patients with gout and/or hyperuricemia (n = 10)	10 mg daily for 2 weeks then 20 mg daily for 4 weeks	Oxidative metabolites 67M-1, 67M-2, and 67M-4 had as parent drug and 40% of drug similar Cmax and tmax was excreted in urine as glucuronic acid conjugate 67-Glu. Data were similar to those reported in healthy male adults
(Hoshide et al 2004)	Healthy subjects and individuals with mild or moderate impairment in renal function (n = 15)	Single dose of 20 mg	The difference in plasma AUC for unchanged febuxostat across the groups was less than 2-fold indicating that renal impairment had little clinical impact on the PK of the drug. Changes in sUA levels from pre-dose levels were not significant
(Mayer et al 2005)	Male and female subjects with normal renal function (n = 11) and with mild (n = 6), moderate (n = 7), or severe renal impairment (n = 7)	80 mg daily dose for 7 days	Plasma exposure to febuxostat and its metaboliteswas generally higher in subjects with increasing degrees of renal impairment, but the % decrease in sUA were comparable regardless of the renal function group. No dose adjustment needed for febuxostat treatment based on differences in renal function
(Khosravan et al 2006a)	Subjects with normal hepatic function (n = 11) and mild (n = 8) and moderate (n = 8) hepatic impairment	80 mg daily dose for 7 days	No statistically or clinically significant differences inthe plasma PK and PD parameters were observed between subjects with mild or moderate hepatic impairment and those with normal hepatic function. No dose adjustment needed in subjects with mild to moderate hepatic impairment
(Khosravan et al 2006c)	Male and female healthy volunteers, study 1 (n = 26); study 2 (n = 24)	In study 1, subjects received febuxostat 80 mg once daily, indomethacin 50 mg twice daily, or both for 5 days. In study 2, subjects received febuxostat 80 mg, naproxen 500 mg twice daily, or both for 7 days	Febuxostat had no effect on the plasma PK ofindomethacin and naproxen. Indomethacin had no effect on the plasma PK of febuxostat. Although naproxen caused an increase in plasma exposure to febuxostat, this increase is not expected to be clinically significant
(Khosravan et al 2008a)	Male and female healthy volunteers (n = 92)	Single 40 mg (n = 24), or multiple 80 mg (n = 24), or single 120 mg (n = 20) in fasting and non-fasting conditions, or single 80 mg (n = 24) doses alone or with antacid	Food caused a decrease in the rate and extent ofabsorption of febuxostat, but this decrease was not associated with a clinically significant change in febuxostat PD effect. Despite a decrease in the absorption rate of febuxostat, antacid had no effect on the extent of febuxostat absorption
(Khosravan et al 2008b)	Healthy male and female subjects (aged 18–40 years or ≥65 years) (n = 96)	80 mg daily dose for 7 days	Age or gender had no clinically significant effect on the PK, PD, or safety of febuxostat

Abbreviations: AUC, area under the plasma concentration-time curve; PD, pharmacodynamic; PK, pharmacokinetic; sUA, serum uric acid.

Figure 1 Chemical structures of (a) febuxostat and metabolites (b) 67M-1, (c) 67M-2, and (d) 67M-4. Adapted with permission from Khosravan R, Grabowski BA, Wu JT, et al. 2006b. Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet, 45:821–41. Copyright © 2006 Wolters Kluwer.

Table 2 Efficacy of febuxostat in phase III and long term clinical trials

Reference	Patients	Study design	Treatment	Outcomes
(Kamatani et al 2004)	256 (Japanese)	R, DB, MC, 8 weeks	FBX 40 mg, ALO	82% of patients in the FBX arm achieved sUA levels of ≤6.0, compared with69% in the ALO arm
(Becker et al 2005a) FACT	762 (77% Caucasian)	R, DB, MC, 52 weeks	FBX 80 mg, 120 mg, ALO 300 mg	53%, 62%, and 21% of patients in FBX80 mg, 120 mg, and ALO 300 mg groups achieved sUA <6 mg/dL, respectively (p < 0.001 for the comparison of each febuxostat group with the allopurinol group) The overall incidence of gout flares was 64% 70%, and 64% for FBX 80 mg, 120 mg, and ALO 300 mg groups, respectively
(Schumacher et al 2005) APEX	1067 (78% Caucasian) including 40 with moderately impaired renal function	R, PC, 28 weeks	Placebo, FBX 80 mg,120 mg, 240 mg, ALO 300 mg/100 mg (depend on renal function)	48%, 65%, 69%, 22%, and 0% of patients in FBX 80 mg, 120 mg, 240 mg, ALO 300/100 mg, and placebo groups achieved sUA <6 mg/dL at each of the last 3 visits, respectively (p < 0.05 for all comparison between groups) and 44%, 45%, 60%, 0%, 0% for subjects with moderate renal impairment for each groups
(Wortmann et al 2006) EXCEL	1086 (79% Caucasian)	R, OL, LT, (an extension study of 2 phase III trials above)	FBX 80 mg, 120 mg, 240 mg, ALO 300 mg/100 mg (depend on renal function)	The incidence of gout flares decreased gradually from 1.4, 1.72, and 1.49 fares per year in the 1st year to 0.19, 0.0, and 0.11 flares per year in the 3rd year for febuxostat 80 mg, 120 mg, and allopurinol 300/100 mg groups, respectively
(Schumacher et al 2006) FOCUS	116 (85% Caucasian) with 61 subjects on continued treatment with ≥48 months	OL, LT	FBX 40 mg, 80 mg,120 mg	Across all doses, the proportion of subjects with sUA <6.0 mg/dL were 78%, 76%, 84%, and 90% at year 1, 2, 3, and 4, respectively. Overall incidence of gout flares requiring treatment declined markedly by 2 years and continued over 4 year of febuxostat treatment. After the 1st year of stable dose, subjects, on average, had <1 gout flare/year

Abbreviations: ALO, allopurinol; DB, double blind; FBX, febuxostat; LT, long term; MC, multicenter; OL, open label; PC, placebo controlled; R, randomized; sUA, serum uric acid.

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