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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?

SUBMITTER: Fukase H

PROVIDER: S-EPMC7066277 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Fukase Hiroyuki H Okui Daisuke D Sasaki Tomomitsu T Fushimi Masahiko M Ohashi Tetsuo T Hosoya Tatsuo T

Clinical and experimental nephrology 20191210 Suppl 1

<h4>Background</h4>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.<h ...[more]

PMID: 31823130

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Project description:Gout is a chronic inflammatory disease caused by precipitation of urate crystals in the joints, kidneys, and urinary tract. Independent of urate deposition disorders, recent studies have shown a positive association between circulating uric acid (UA) levels and cardiovascular (CV) diseases. These results indicate that UA is a precipitating factor of both gout and the progression of CV diseases, including hypertension and/or chronic kidney disease (CKD). A large body of evidence has shown that UA-lowering therapies are effective in preventing the progression of hypertension/CKD and that a causal relationship exists between serum UA level and CV diseases. Despite the urgent need for effective UA-lowering drugs that can be used to obtain better therapeutic outcomes and prognosis, only few drugs have been developed in the past decades. Recently, febuxostat and topiroxostat, which are xanthine oxidoreductase inhibitors, were developed and used in clinical practice. Of note, after the approval of lesinurad, which is a urate transporter-1 (URAT-1) inhibitor, in the United States in 2015, dotinurad (Fig. 1), a novel promising drug with selective UA reabsorption inhibitory property, was recently developed in Japan in 2018. Dotinurad is indicated for patients with hyperuricemia/gout as most patients with hyperuricemia are classified into "underexcretion type", which requires the inhibition of URAT-1 to excrete excess UA via the kidney. Focusing on dotinurad, the present study highlighted the multifaceted preliminary new trials that assessed for drug efficacy and safety, pharmacokinetics (PK) according to age and gender, the presence or absence of liver and kidney disorders, drug interactions with NSAID, and non-inferiority of dotinurad to either febuxostat or benzbromarone. A series of studies included in this supplemental review indicate that dotinurad reduces serum UA levels, and its efficacy and safety are similar to those of other UA-lowering agents currently used even in hyperuricemic patients with various clinical conditions. Moreover, two exploratory studies with a small sample size were conducted to compare PK parameters between patients with overproduction- and underexcretion-type hyperuricemia, and results showed that the effects of UA-lowering agents were comparable between the two subtype groups.Fig. 1Chemical structural formula of dotinurad.

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

Publications

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

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