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      Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy Japanese and non-Asian male subjects

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          Abstract

          Purpose

          Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of gout and asymptomatic hyperuricemia. This study evaluated verinurad pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and non-Asian adult male subjects.

          Methods

          This was a Phase I, randomized, single-blind, placebo-controlled study. Panels of 8 Japanese subjects were randomized to receive oral verinurad (2.5–15 mg) or placebo administered as a single dose in a fasted and fed state and as once-daily doses for 7 days in a fed state. Eight non-Asian subjects received verinurad 10 mg as a single dose (fasted and fed) and multiple doses in the fed state. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events and laboratory data.

          Results

          Of 48 randomized subjects, 46 (Japanese, 39; non-Asian, 7) completed the study. Following single or multiple doses in Japanese subjects, maximum plasma concentration ( C max) and area under the plasma concentration–time curve (AUC) increased in a near dose-proportional manner. Time to C max ( T max) was ~1.25–2.0 hours with fasting. A moderate-fat meal delayed T max (range 3.0–5.0 hours) and had a variable effect on AUC (0%–97% increase) and C max (0%–26% increase) across the dose groups. Following multiple verinurad 10 mg doses, C max and AUC were 38% and 23% higher, respectively, in Japanese vs non-Asian subjects, largely due to body weight differences. Mean reduction of serum urate following multiple verinurad 10 mg doses was 46% and 44% after 24 hours in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses.

          Conclusion

          Verinurad monotherapy lowered serum urate and was well tolerated in both healthy Japanese and non-Asian males, while small differences in plasma pharmacokinetics were observed. These data support further evaluation of once-daily verinurad as a treatment for gout and asymptomatic hyperuricemia.

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          Most cited references 16

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          Clinical practice. Gout.

           Tuhina Neogi (2011)
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            Japanese guideline for the management of hyperuricemia and gout: second edition.

             Hisashi Yamanaka,   (2011)
            Gout is a urate deposition disease caused by persistent hyperuricemia. Because gout patients present with a variety of clinical symptoms, it is necessary to have a guideline for the standard management and care of gout and hyperuricemia. The Japanese Society of Gout and Nucleic Acid Metabolism, a scientific society committed to study nucleic acid metabolism and related diseases, established the first edition of the "Guideline for the Management of Hyperuricemia and Gout" in 2002, and published the revised version in January 2010. This second edition is not only evidence based on a search of systemic literature, but also includes consensus levels by a Delphi exercise to determine the strength of the recommendations. A draft version of this guideline was reviewed by internal and external reviewers as well as a patient. In this guideline, key messages from each chapter are listed as statements together with the evidence level, consensus level, and strength of the recommendation. In this proceeding, several selected chapters on the clinical management of gout and hyperuricemia are described. We hope this guideline is appropriately used for the standard management and care of patients with hyperuricemia and gout in daily practice.
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              Gout: why is this curable disease so seldom cured?

              Gout is the most common inflammatory arthritis and one in which pathogenesis and risk factors are best understood. One of the treatment objectives in current guidelines is 'cure'. However, audits show that only a minority of patients with gout receive adequate advice and treatment. Suboptimal care and outcomes reflect inappropriately negative perceptions of the disease, both in patients and providers. Historically, gout has been portrayed as a benign and even comical condition that is self-inflicted through overeating and alcohol excess. Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Urate-lowering treatment is underprescribed and often underdosed. Appropriate education of patients and doctors, catalysed by recent introduction of new urate-lowering treatments after many years with no drug development in the field, may help to overcome these barriers and improve management of this easily diagnosed and curable form of potentially severe arthritis.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                20 June 2018
                : 12
                : 1799-1807
                Affiliations
                [1 ]Ardea Biosciences, Inc., San Diego, CA, USA
                [2 ]AstraZeneca, Gaithersburg, MD, USA
                Author notes
                Correspondence: Jesse Hall, Ardea Bisociences, Inc., 9390 Towne Center Dr, San Diego, CA 92121, USA, Tel +1 858 652 6500, Email jhall@ 123456ardeabio.com
                Article
                dddt-12-1799
                10.2147/DDDT.S152659
                6018888
                © 2018 Hall et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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