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Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study

OBJECTIVES: Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allop...

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Autores principales: Fleischmann, Roy, Winkle, Peter, Miner, Jeffrey N, Yan, Xiaohong, Hicks, Liz, Valdez, Shakti, Hall, Jesse, Liu, Sha, Shen, Zancong, Gillen, Michael, Hernandez-Illas, Martha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845419/
https://www.ncbi.nlm.nih.gov/pubmed/29531784
http://dx.doi.org/10.1136/rmdopen-2017-000584
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author Fleischmann, Roy
Winkle, Peter
Miner, Jeffrey N
Yan, Xiaohong
Hicks, Liz
Valdez, Shakti
Hall, Jesse
Liu, Sha
Shen, Zancong
Gillen, Michael
Hernandez-Illas, Martha
author_facet Fleischmann, Roy
Winkle, Peter
Miner, Jeffrey N
Yan, Xiaohong
Hicks, Liz
Valdez, Shakti
Hall, Jesse
Liu, Sha
Shen, Zancong
Gillen, Michael
Hernandez-Illas, Martha
author_sort Fleischmann, Roy
collection PubMed
description OBJECTIVES: Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. METHODS: Forty-one subjects were randomised into two cohorts of verinurad (2.5–20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid. RESULTS: Serum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (E(max)) at 7–12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means E(max) was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol C(max) by 19.0%–32.4% and area under the plasma concentration–time curve from time zero to the last measurable time point by 20.8%–39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes. CONCLUSION: Verinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. TRIAL REGISTRATION NUMBER: NCT02498652.
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spelling pubmed-58454192018-03-12 Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study Fleischmann, Roy Winkle, Peter Miner, Jeffrey N Yan, Xiaohong Hicks, Liz Valdez, Shakti Hall, Jesse Liu, Sha Shen, Zancong Gillen, Michael Hernandez-Illas, Martha RMD Open Crystal Arthropathies OBJECTIVES: Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. METHODS: Forty-one subjects were randomised into two cohorts of verinurad (2.5–20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid. RESULTS: Serum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (E(max)) at 7–12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means E(max) was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol C(max) by 19.0%–32.4% and area under the plasma concentration–time curve from time zero to the last measurable time point by 20.8%–39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes. CONCLUSION: Verinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. TRIAL REGISTRATION NUMBER: NCT02498652. BMJ Publishing Group 2018-02-08 /pmc/articles/PMC5845419/ /pubmed/29531784 http://dx.doi.org/10.1136/rmdopen-2017-000584 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
spellingShingle Crystal Arthropathies
Fleischmann, Roy
Winkle, Peter
Miner, Jeffrey N
Yan, Xiaohong
Hicks, Liz
Valdez, Shakti
Hall, Jesse
Liu, Sha
Shen, Zancong
Gillen, Michael
Hernandez-Illas, Martha
Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
title Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
title_full Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
title_fullStr Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
title_full_unstemmed Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
title_short Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
title_sort pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase iia, open-label study
topic Crystal Arthropathies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845419/
https://www.ncbi.nlm.nih.gov/pubmed/29531784
http://dx.doi.org/10.1136/rmdopen-2017-000584
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