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

Abstract

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.

Keywords: Dotinurad; Pharmacodynamics; Pharmacokinetics; Renal dysfunction; Selective urate reabsorption inhibitor; URAT1 inhibitor.

Conflict of interest statement

Fuji Yakuhin Co., Ltd. (Fuji) the manufacturer of dotinurad sponsored this study. TH was an advisor to Fuji regarding this study and received consultant and manuscript fees. HF was principal investigator to this study and received manuscript fees. The other authors were employees of Fuji.

Figures

Fig. 1

The time-course of concentration of dotinurad. Error bars indicate standard deviation

Fig. 2

The time-course of serum uric acid concentrations. Error bars indicate standard deviation

Fig. 3

Change in urinary uric acid excretion. Error bars indicate standard deviation