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Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects

PURPOSE: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. SUBJECTS...

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Autores principales: Shen, Zancong, Gillen, Michael, Miner, Jeffrey N, Bucci, Gail, Wilson, David M, Hall, Jesse W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511024/
https://www.ncbi.nlm.nih.gov/pubmed/28744099
http://dx.doi.org/10.2147/DDDT.S140658
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author Shen, Zancong
Gillen, Michael
Miner, Jeffrey N
Bucci, Gail
Wilson, David M
Hall, Jesse W
author_facet Shen, Zancong
Gillen, Michael
Miner, Jeffrey N
Bucci, Gail
Wilson, David M
Hall, Jesse W
author_sort Shen, Zancong
collection PubMed
description PURPOSE: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. SUBJECTS AND METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10–12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). RESULTS: A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (C(max)) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner; C(max) occurred at 0.5–0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and C(max) by 37%−53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. CONCLUSION: Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.
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spelling pubmed-55110242017-07-25 Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects Shen, Zancong Gillen, Michael Miner, Jeffrey N Bucci, Gail Wilson, David M Hall, Jesse W Drug Des Devel Ther Original Research PURPOSE: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. SUBJECTS AND METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10–12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). RESULTS: A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (C(max)) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner; C(max) occurred at 0.5–0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and C(max) by 37%−53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. CONCLUSION: Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout. Dove Medical Press 2017-07-07 /pmc/articles/PMC5511024/ /pubmed/28744099 http://dx.doi.org/10.2147/DDDT.S140658 Text en © 2017 Shen 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.
spellingShingle Original Research
Shen, Zancong
Gillen, Michael
Miner, Jeffrey N
Bucci, Gail
Wilson, David M
Hall, Jesse W
Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects
title Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects
title_full Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects
title_fullStr Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects
title_full_unstemmed Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects
title_short Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects
title_sort pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511024/
https://www.ncbi.nlm.nih.gov/pubmed/28744099
http://dx.doi.org/10.2147/DDDT.S140658
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