An extended release formulation of febuxostat (Uloric) was effective for reducing uric acid in patients with gout, including patients who had renal impairment, a phase III trial found.
Significantly more patients randomized to febuxostat, both in extended release (XR) and immediate release (IR) formulations and in 40 mg/day and 80 mg/day dosages, achieved a serum uric acid level below 5 mg/dL at month 3 compared with patients receiving placebo, according to Kenneth G. Saag, MD, of the University of Alabama at Birmingham, and colleagues.
In addition, more patients receiving the XR 40 mg dose had serum uric acid levels below 5 mg/dL at 3 months compared with those given IR 40 mg (25.9% versus 15.7%, P=0.001), the investigators reported online in Arthritis & Rheumatology.
Moreover, that goal was reached by patients with mild and moderate renal impairment receiving XR 40 mg (29.1% and 26.9%) which were significantly greater proportions than among those receiving IR 40 mg (16.1% and 13.2%, P<0.05 for both).
Febuxostat and allopurinol both lower uric acid through inhibition of xanthine oxidase, but allopurinol is cleared through renal pathways and febuxostat is eliminated through the liver, and previous small studies have suggested that febuxostat also was effective in patients with renal impairment.
“To reduce the potential risk of treatment-initiated gout flares caused by fluctuations in drug exposure levels with febuxostat IR, an extended release formulation of febuxostat was developed, with the aim of providing comparable or greater urate lowering with more stable drug exposure,” Saag and colleagues wrote.
Therefore, to assess the efficacy and safety of the XR formulation, the investigators enrolled 1,783 patients from 217 U.S. centers from 2015 to 2016, randomizing them to placebo or oral febuxostat IR 40 mg, XR 40 mg, IR 80 mg, or XR 80 mg for 3 months. All participants also were given gout flare prophylaxis with colchicine or naproxen plus lansoprazole.
Because greater uric acid reductions were expected for the XR formulations based on pharmacokinetic and pharmacodynamic data, the primary endpoint was reduction below 5 mg/dL rather than the standard 6 mg/dL goal, which was a secondary endpoint.
Normal renal function was defined as an estimated glomerular filtration rate of 90 mL/min or higher. Mild impairment was 60-89 mL/min, moderate was 30-59 mL/min, and severe was 15-29 mL/min.
The mean age of the patients was 55, more than 80% were men, and two-thirds were white. Baseline serum uric acid was 9.6 mg/dL.
Both formulations and doses of febuxostat were associated with greater numbers of patients achieving serum uric acid below 6 mg/dL compared with placebo. A greater proportion of patients with mild renal impairment given the XR 40 mg formulation reached uric acid levels below 6 mg/dL compared with the IR 40 mg formulation (49.5% versus 38%, P=0.016).
The investigators also noted that the IR 80 mg dose was more effective than the XR 40 mg dose in all renal impairment groups, even the severely impaired, in whom the goal of below 5 mg/dL was achieved by 35% versus 14.3% (P<0.05). This suggested that “dose titration from febuxostat IR 40 mg to febuxostat IR 80 mg would potentially represent a more effective treatment strategy than switching to febuxostat XR 40 mg,” the team wrote.
The proportion of patients who experienced a gout flare during the treatment study period was similar across renal function subgroups regardless of treatment group.
A total of 38.8% of patients experienced any adverse event, with most being mild or moderate and no particular pattern was observed for dosages or formulations. The most common events were diarrhea, nasopharyngitis, and hypertension.
Two cases of renal failure were reported — one each in the XR 40 mg and IR 40 mg groups, and one acute kidney injury in the XR 40 group.
There were three deaths, one of which was considered treatment-related. This was a case of cardiorespiratory arrest in a patient with severe renal impairment receiving IR 80 mg.
Limitations of the study, the researchers said, included the small numbers of patients in some renal subgroups and the fact that flare prophylaxis was given, which may have interfered with the possibility of detecting differences between the XR and IR formulations.
The study was sponsored by Takeda Pharmaceuticals International.
The authors reported financial relationships with Takeda, Ardea/AstraZeneca, Horizon, SOBI, Ironwood, and CymaBay, and several are employees of Takeda.
Dori F. Zaleznik, MD Associate Clinical Professor of Medicine (Retired), Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner