Pharmacodynamic modeling of uric acid turnover and the effect of Verinurad (RDEA3170), a novel selective uric acid reabsorption inhibitor for the treatment of gout and asymptomatic hyperuricemia
Jacob Leander (1), Sergey Aksenov (2), Jesse Hall (3), Ulf Eriksson (1)
(1) Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Sweden, (2) Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Waltham, United States, (3) Ardea Biosciences, San Diego, United States
Objectives: Verinurad (RDEA3170) inhibits the uric acid transporter URAT1 that is responsible for most of the reabsorption of uric acid from the renal tubule. A pharmacokinetic-pharmacodynamic model was developed and qualified to predict dose-response of verinurad for lowering of serum uric acid both alone and in combination with the xanthine oxidase inhibitor febuxostat.
Methods: Measurements of plasma drug concentrations and uric acid concentrations in serum and urine were obtained in 513 subjects from 11 clinical studies. The clinical data included both single and multiple dose data in healthy volunteers and hyperuricemic gout patients.
An indirect response model was developed that incorporated the relevant aspects of uric acid turnover, including intestinal and renal elimination and reabsorption of uric acid [1]. The verinurad effect on renal reabsorption of uric acid and febuxostat effect on production of uric acid was described by inhibitory expressions dependent on the respective plasma drug concentrations.
The model was developed in NONMEM 7.3.0 [2], to allow estimation of individual variability in parameters of uric acid turnover and drug effects.
Results: The uric acid model describes the data well and clinically relevant serum uric acid lowering was seen for the lowest studied dose of verinurad. Moreover, the model describes the difference in uric acid turnover between healthy volunteers and patients. In patients, the estimated production rate was higher (51.5 mg/h versus 36.2 mg/h) and the estimated fractional excretion of uric acid was lower (0.049 versus 0.056).
Dose-response simulations show that for verinurad doses in the range 2.5-10 mg serum uric acid levels are reduced by 20-45% on top of febuxostat mono therapy.
Model simulations for patients with varying renal function showed that impaired renal function was associated with higher serum uric acid level and lower renal excretion rate before treatment. Moreover, simulations show that the relative decrease in serum uric acid concentration following verinurad treatment is decreased in patients with impaired renal function, which is consistent with verinurad’s renal based mechanism of uric acid lowering.
Conclusions: The uric acid model enables a quantitative approach for assessing dose-response for the effect of verinurad alone and in combination with febuxostat on serum uric acid and urinary uric acid excretion rate that can support dose selection in clinical trials of verinurad.
References:
[1] Aksenov, S., Eriksson, U., Stanski, D., 2016. Physiological modeling of uric acid in man: application to assess benefit-risk of lesinurad in gout. 7th American Conference for Pharmacometrics (ACoP7). Seattle, USA. J Pharmacokinet Pharmacodyn. 43(Suppl 1): 11
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.