A semi-mechanistic exposure\u2013response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases

Jacob Leander,Ulf G Eriksson,Mikael Sunnåker,Joanna Parkinson,Sergey Aksenov,Susanne Johansson,Dinko Rekić

doi:10.1007/s10928-021-09747-y

Jacob Leander, Ulf G Eriksson + Show 5 more

Open Access

https://doi.org/10.1007/s10928-021-09747-y

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Abstract

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.

Highlights

Hyperuricemia, defined as elevated serum uric acid levels, has been linked to an increased risk of kidney disease, hypertension, coronary heart disease, cardiovascular mortality, and diabetic retinopathy [1,2,3,4,5,6,7]
Coadministration 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
Symptomatic hyperuricemic 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

Summary

Introduction

Hyperuricemia, defined as elevated serum uric acid (sUA) levels, has been linked to an increased risk of kidney disease, hypertension, coronary heart disease, cardiovascular mortality, and diabetic retinopathy [1,2,3,4,5,6,7]. These discoveries raised the question of whether sUA lowering therapy would improve patient outcomes; at present there is no clear and consistent evidence that sUA lowering translates into cardiovascular and renal benefits, with some trials reporting improvement in patients, while others showing no benefit or even worsening [8,9,10]. In addition to URAT1, solute carrier family 2 facilitated glucose transporter member 9 (GLUT9) and organic iron transporter 4 (OAT4) reabsorb uric acid from the renal tubular lumen back to the systemic circulation

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