Comparison of Clinical Advantage between Topiroxostat and Febuxostat in Hemodialysis Patients

Abstract

To determine the response of hemodialysis (HD) patients to topiroxostat after a switch from febuxostat, we evaluated the efficacy, tolerability, and serum concentration of topiroxostat in HD patients after the switch. In this 16-month prospective observational study, we assessed the serum uric acid (UA) levels, other laboratory data, and serum topiroxostat concentrations of 10 HD patients who had been receiving febuxostat at a dose of 10 mg/d for over 1 year. No statistical difference was observed between the tolerability index at baseline and 16 months after the switch to topiroxostat. Serum UA after the switch in all patients (attained serum UA levels of ≤6 mg/dL) was 5.6 1.7 mg/dL (60%) at baseline, 4.9 0.5 mg/dL (100%) at 6 months and 5.7 0.4 mg/dL (50%) at 16 months (p 0.25), respectively. In patients with baseline serum UA levels >6 mg/dL, serum UA was significantly reduced at 6 and 16 months compared with baseline. Minimum serum concentrations of serum topiroxostat were lower than the limit of quantification (<25 ng/mL). Our results indicate that a switch from febuxostat 10 mg/d to topiroxostat 40 mg/d might reduce serum UA levels, with no change in other clinical laboratory data over the long term. These effects were more frequent in patients with high serum UA levels. Furthermore, topiroxostat therapy was more cost effective than febuxostat therapy. Thus, topiroxostat therapy could be a better treatment option for HD patients who develop high serum UA levels after febuxostat 10 mg/d administration.Key words topiroxostat; febuxostat; hemodialysis; serum uric acid level; serum concentration Elevated serum uric acid (UA) levels (hyperuricemia) are known to be associated with comorbid conditions such as cardiovascular disease (CVD), chronic kidney disease (CKD) and hypertension.1) CVD is associated with risks of morbidity and mortality in hemodialysis (HD) patients, 2) and CKD patients receive urate-lowering therapy, mainly in the form of xanthine oxidase (XO) inhibitors. 3)One of these XO inhibitors is topiroxostat, whose primary metabolite is topiroxostat N-glucuronide. 4) In a multicenter, double-blind randomized controlled trial comparing the XO inhibitors topiroxostat 120 mg/d and allopurinol 200 mg/d in Japanese hyperuricemic patients with or without gout, topiroxostat showed a non-inferior decrease in serum UA levels compared with allopurinol and was well tolerated (change in serum urate levels of −36.3 vs. −34.3%, respectively).5) In another study involving hyperuricemic stage 3 CKD patients with or without gout, topiroxostat 160 mg reduced serum UA levels (−45.3%) and urinary albumin-to-creatinine ratio (−33.0%) over 22 weeks. 6) Also, in HD patients receiving topiroxostat therapy, serum UA levels were reduced from 9 to 5 mg/dL and the serum concentrations of topiroxostat were 25 ng/mL before HD sessions. 7)Febuxostat is another XO inhibitor, with febuxostat acylglucuronide as its primary metabolite. 8) Population pharmacokinetics and therapeutic analysis of febuxostat have revealed that severe ren...

Discovery of coumaric acid derivatives hinted by coastal marine source to seek for uric acid lowering agents

“…Allopurinol was most widely used with the structural similarity to purine, thus it could cause various undesired adverse effects 22 . Free from the purine moiety, Febuxostat and Topiroxostat could bind into the active site of XO, which inspired the rational strategies such as fragment-based drug design (FBDD) 23 , 24 . Besides, during the discovery of potential XO inhibitors, both the potency and the safety should be seriously concerned.…”