Verinurad, a potent inhibitor of uric acid transporter 1 (URAT1), reduces serum uric acid levels by enhancing its renal excretion. When coadministered with a xanthine oxidase inhibitor (XOI), which simultaneously lowers uric acid production, the risk of renal tubular precipitation of uric acid—potentially leading to acute kidney injury—is minimized. This combination is currently under development for chronic kidney disease and heart failure. The objective of this study was to extend a previously developed semi-mechanistic exposure-response model for uric acid kinetics to incorporate interindividual variability in response to verinurad and its combinations with XOIs, and to generate predictive insights to guide future clinical dosing strategies.
The model was developed using data from 12 clinical studies involving 434 individuals, including healthy volunteers, patients with hyperuricemia, and those with renal impairment. It effectively captured the dynamics of uric acid handling across diverse populations, accounting for key patient characteristics such as renal function, baseline fractional excretion of uric acid (FEUA), and race. The estimated half-maximal effective concentrations (EC50) were 29.4 ng/mL for verinurad (reducing uric acid reabsorption), 128 ng/mL for febuxostat (reducing production), and 13,030 ng/mL for oxypurinol (active metabolite of allopurinol). Symptomatic hyperuricemic (gout) patients exhibited a higher EC50 for verinurad (37.3 ng/mL) compared to healthy volunteers (29.4 ng/mL), while no significant difference was observed in asymptomatic hyperuricemics. Baseline FEUA was significantly lower in symptomatic hyperuricemic patients (5.6%) than in healthy subjects (9.1%), and Asian participants showed slightly reduced FEUA (4.3% vs. 5.6% in symptomatic patients).
Model simulations were conducted to evaluate dose-response relationships for verinurad in combination with XOIs and to assess the influence of covariates such as eGFR, body weight, and race. Results indicated that a 12 mg extended-release verinurad dose combined with 80 mg febuxostat or 300 mg allopurinol achieved substantial reductions in serum uric acid (sUA), with maximal sUA reduction exceeding 70% at steady state. Notably, the addition of an XOI significantly lowered the maximum urinary uric acid (uUA) excretion rate compared to verinurad monotherapy, reducing the risk of crystallization. Simulations further revealed that even at lower doses of XOI (e.g., 60–80 mg febuxostat), uUA excretion remained within safe physiological ranges, whereas monotherapy with verinurad led to a marked increase in excretion rates.
The model demonstrated strong predictive performance, validated against an independent dataset (study D5495C00006), confirming its utility in supporting clinical decision-making. Importantly, no clinically relevant impact of renal function, body weight, or race on efficacy or safety endpoints was identified, suggesting that uniform dosing regimens may be appropriate across these subpopulations.TUBB2B Antibody Purity & Documentation The integration of mechanistic pharmacokinetic-pharmacodynamic principles enabled the evaluation of untested dose combinations without requiring additional clinical trials, highlighting the model’s value in optimizing treatment regimens.TIA1 Antibody Protocol
This work provides a robust quantitative framework for understanding the effects of verinurad and its combination therapy in hyperuricemia-associated diseases.PMID:35217790 By balancing efficacy and safety through simulation-based predictions, the model supports rational dose selection and enhances confidence in advancing verinurad into later-stage development for conditions such as chronic kidney disease and heart failure.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
