A semi-mechanistic exposure–response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases
| العنوان: | A semi-mechanistic exposure–response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases |
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| المؤلفون: | Susanne Johansson, Ulf Eriksson, Joanna Parkinson, Mikael Sunnåker, Jacob Leander, Sergey Aksenov, Dinko Rekić |
| المصدر: | Journal of Pharmacokinetics and Pharmacodynamics |
| بيانات النشر: | Springer US, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Verinurad, Male, Pyridines, Organic Anion Transporters, 030204 cardiovascular system & hematology, Pharmacology, urologic and male genital diseases, Kidney, PKPD, chemistry.chemical_compound, 0302 clinical medicine, Hyperuricemia, Xanthine oxidase inhibitor, Aged, 80 and over, Middle Aged, Drug Therapy, Combination, Female, Febuxostat, Mixed effects modeling, medicine.drug, Adult, Xanthine Oxidase, Organic Cation Transport Proteins, medicine.drug_class, Allopurinol, Renal function, Naphthalenes, Excretion, 03 medical and health sciences, Young Adult, medicine, Humans, Semi-mechanistic modeling, Aged, 030203 arthritis & rheumatology, Original Paper, Models, Statistical, business.industry, medicine.disease, Gout, Uric Acid, chemistry, Uric acid, URAT1, Propionates, business |
| الوصف: | Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure–response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose–response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad. Supplementary Information The online version contains supplementary material available at 10.1007/s10928-021-09747-y. |
| اللغة: | English |
| تدمد: | 1573-8744 1567-567X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::574e640a5a011361b8c579a602261ba7 http://europepmc.org/articles/PMC8225519 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....574e640a5a011361b8c579a602261ba7 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 15738744 1567567X |
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