Clinical pharmacological study of dotinurad administered to male and female elderly or young subjects.

BACKGROUND: Dotinurad is a novel selective urate reabsorption inhibitor (SURI) that selectively inhibits the reabsorption of uric acid in renal tubules and promotes the excretion of uric acid into urine. In this study, the effects of age and gender on the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad were evaluated in healthy subjects. METHODS: An open-label study of a single oral administration of dotinurad 1 mg was conducted in elderly (≥ 65 years) Japanese males and females, and young (20-35 years) males and females (six patients each). RESULTS: Following a single-dose administration of dotinurad, the change in dotinurad plasma concentration showed a similar profile across groups. Regarding the PK parameters, there was no significant difference between elderly and young subjects. On comparing males and females, significant differences were observed in some parameters in elderly subjects. However, these differences in some parameters could not be detected by adjust for body weight. When PD parameters in elderly and young subjects were compared, significant differences were observed in some parameters in male subjects. On comparing males and females, significant differences were observed in some parameters in young subjects; however, the percent change in serum uric acid concentration decreased over time was relatively close for both groups. There were no clinically relevant safety problems. CONCLUSION: Age and gender had no clinically meaningful effect on the PK, PD, and safety of dotinurad. CLINICAL TRIALS: ClinicalTrials.gov identifier: NCT02344875.

Open-label study of long-term administration of dotinurad in Japanese hyperuricemic patients with or without gout.

BACKGROUND: Dotinurad is a novel selective urate reabsorption inhibitor (SURI) which reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1). This study was intended to verify the efficacy and safety of dotinurad following treatment for 34 or 58 weeks in hyperuricemic patients with or without gout. METHODS: This long-term study had an open-label design with dose escalation. The dose of dotinurad started at 0.5 mg/day and was increased progressively to 2 mg/day. If the serum uric acid level of patients did not reach ≤ 6 mg/dL at week 14, the dose was increased to 4 mg/day. The primary endpoint was the percent change in serum uric acid level from the baseline to each visit. RESULTS: At a dose of 2 mg, serum uric acid levels at week 34 and 58 were reduced from the baseline by 46.73% and 47.17%, respectively; at 4 mg, the respective values were 54.92% and 57.35%. At week 34 and 58, the percentages of patients achieving a serum uric acid levels ≤ 6.0 mg/dL with 2-mg dose were 89.11% and 91.30%, respectively; with 4 mg, the respective rates were 97.50% and 100.00%. In addition, the incidences of adverse events and adverse drug reactions were 65.2% and 21.8%, respectively. CONCLUSION: Dotinurad at doses of 2-4-mg sufficiently reduced serum uric acid levels in hyperuricemic patients with or without gout, and its efficacy and safety were verified for long-term administration. ClinicalTrials.gov Identifier: NCT03006445.

The effect for hyperuricemia inpatient of uric acid overproduction type or in combination with topiroxostat on the pharmacokinetics, pharmacodynamics and safety of dotinurad, a selective urate reabsorption inhibitor.

BACKGROUND: Dotinurad, a novel selective urate reabsorption inhibitor (SURI), increases urinary uric acid excretion. The aim of this study is to examine the pharmacokinetics, pharmacodynamics, and safety of dotinurad according to the type of hyperuricemia, with or without concomitant use of xanthine oxidase inhibitor, in uric acid "overproduction type" patients. METHODS: This open-label clinical pharmacology study was conducted in a hospital. Dotinurad 1 mg was administered for 7 days to hyperuricemic patients with uric acid "overproduction type" (overproduction group, n = 6; and combination group, n = 6) and uric acid "underexcretion type" (underexcretion group, n = 6). In the combination group, topiroxostat 80 mg was used concomitantly. RESULTS: No significant differences were observed in pharmacokinetics and safety between overproduction group and underexcretion group, and the percent change in serum uric acid level and the amount of urinary uric acid excretion after administration were comparable. In "overproduction type" patients of combination group, the percent change in serum uric acid level significantly increased and the amount of urinary uric acid excretion significantly decreased compared to those of overproduction group. No clinically meaningful differences were observed in safety between the overproduction group and the combination group. CONCLUSION: In inpatients, differences in hyperuricemic type did not significantly influence the pharmacokinetics, pharmacodynamics, and safety of dotinurad. Moreover, in "overproduction type", the coadministration of dotinurad and topiroxostat had an add-on serum uric acid lowering effect and suppressed urinary uric acid excretion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02837198.

Effects of mild and moderate renal dysfunction on pharmacokinetics, pharmacodynamics, and safety of dotinurad: a novel selective urate reabsorption inhibitor.

BACKGROUND: Dotinurad, a novel selective urate reabsorption inhibitor, exerts a serum uric acid-lowering effect by selectively inhibiting urate transporter 1 (URAT1) in patients with hyperuricemia. It is generally known that the progression of renal dysfunction is associated with a reduction in the serum uric acid-lowering effects of uricosuric drugs. We, therefore, investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with renal dysfunction. METHODS: This was a parallel-group, open-label, single-dose clinical pharmacology study. Dotinurad (1 mg) was administered once, orally to subjects with mild (estimated glomerular filtration rate [eGFR], ≥ 60 to < 90 mL/min/1.73 m2) or moderate (eGFR, ≥ 30 to < 60 mL/min/1.73 m2) renal dysfunction or normal (eGFR, ≥ 90 mL/min/1.73 m2) renal function. RESULTS: The time-course of mean plasma concentration of dotinurad had similar profiles across the groups. Regarding PK, there was no significant difference between the renal dysfunction groups and normal renal function group. Regarding PD, the maximum reduction rate in serum uric acid levels and the fractional uric acid excretion (FE) ratio (FE0-24/FE-24-0) were significantly lower in the moderate renal dysfunction group than in the normal renal function group. However, other PD parameters were not significantly different among the groups. No notable adverse events or adverse drug reactions were observed in this study. CONCLUSION: These results suggested that no dose adjustment might be necessary when administering dotinurad to patients with mild-to-moderate renal dysfunction. ClinicalTrials.gov Identifier: NCT02347046.

Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study).

BACKGROUND: Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in diabetic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study. METHODS: The study design was randomized, double-blind, placebo-controlled, parallel-group study. A total of 65 patients with hyperuricemia and diabetic nephropathy with microalbuminuria were enrolled and assigned to either the topiroxostat group or the placebo group. Topiroxostat (stepwise dosing from 40 to 160 mg/day) or matching placebo was administered BID for 28 weeks. The primary endpoint was a change in the urinary albumin-to-creatinine ratio in the first-morning-void urine sample. Secondary endpoints were changes in the estimated glomerular filtration rate and the serum uric acid level. RESULTS: At 28 weeks, there was no significant difference in the percent change from baseline in the urinary albumin-to-creatinine ratio between the two groups (topiroxostat: 0 vs. placebo: 17%, p = 0.3206), but the changes in the estimated glomerular filtration rate (- 0.2 vs. - 4.0 mL/min/1.73 m2, p = 0.0303) and the serum uric acid level (- 2.94 vs. - 0.20 mg/dL, p < 0.0001) were significantly different between the topiroxostat and placebo groups. Gouty arthritis occurred in 1 patient in the placebo group and no patients in the topiroxostat group. CONCLUSION: These findings support that diabetic nephropathy combined with hyperuricemia may be associated with kidney dysfunctions. Topiroxostat provides strict control of the serum uric acid level preventing decline of eGFR in these patients.