A drug-drug interaction study of a novel, selective urate reabsorption inhibitor dotinurad and the non-steroidal anti-inflammatory drug oxaprozin in healthy adult males

Abstract

Background: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical studies indicated the possibility that the concomitant use of the non-steroidal anti-inflammatory drug oxaprozin affects the pharmacokinetics of dotinurad. We evaluated drug-drug interactions with respect to the pharmacokinetics and safety of dotinurad when co-administered with oxaprozin.

Methods: This was an open-label, two-period, add-on study in healthy adult males. For a single dose of 4 mg of dotinurad with and without oxaprozin, we compared its pharmacokinetic parameters and evaluated safety.

Results: This study enrolled 12 subjects, 11 of whom completed the study. The geometric mean ratio (90% confidence interval [CI]) of the urinary excretion rate of glucuronate conjugates of dotinurad after co-administration with oxaprozin compared to administration of dotinurad alone was 0.657 (0.624-0.692), while the geometric mean ratios (90% CIs) of the maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) were 0.982 (0.945-1.021) and 1.165 (1.114-1.219), respectively. During the study, two adverse events occurred after administration of dotinurad alone and one occurred after administration of oxaprozin alone.

Conclusions: In comparison with administration of dotinurad alone, co-administration with oxaprozin was associated with a 34.3% decrease in the urinary excretion rate of the glucuronate conjugates of dotinurad, and a 16.5% increase in AUC0-inf of dotinurad. However, no clinically meaningful drug-drug interactions were observed. Administration of dotinurad alone was similar safety to co-administration with oxaprozin.

Clinical trial registration: ClinicalTrials.gov Identifier: NCT03350386.

Keywords: Dotinurad; Drug–drug interaction; FYU-981; Pharmacokinetics; Selective urate reabsorption inhibitor (SURI); Urate transporter 1 (URAT1).

Conflict of interest statement

YK received honoraria unrelated to this study from Teijin Pharma Limited. KF received consultant fees unrelated to this study from Kissei Pharmaceutical Co., Ltd. and SRL, Inc. KN and AH were employees of Mochida Pharmaceutical Co., Ltd.

Figures

Fig. 1

Study design

Fig. 2

Subject disposition

Fig. 3

Mean (± SD) plasma concentration versus time point for dotinurad. SD standard deviation

Fig. 4

Mean (± SD) cumulative urinary excretion rate versus end time point of urine collection interval for metabolites of dotinurad. SD standard deviation