S5 Drug Efficacy associated with Renal Apical Transporters

Caroline Lee , Ardea Biosciences, Inc, San Diego, CA
Lesinurad is an URAT1 inhibitor recently approved for the treatment of hyperuricemia associated with gout. Uric acid is the end product of purine metabolism in humans. Circulating serum urate is maintained via its production in the liver and elimination by the kidney and intestine. About 70% of uric acid is eliminated via the kidney with 30% secreted in the small intestine that undergoes metabolism by gut bacteria. Circulating serum urate is filtered and actively transported into the kidney with about 90% reabsorbed from the urine to the blood via URAT1(apical) and Glut9(basolateral). Hyperuricemia is the result of overproduction and under excretion of uric acid. Patients suffering from gout tend to under excrete uric acid by the kidney resulting in high circulating levels of urate (hyperuricemia defined as > 6.8 mg/dL). Lesinurad inhibits URAT1 which reduces uric acid reabsorption thereby lowering serum urate. Since URAT1 is located on the apical side (lumen) of the kidney proximal tubule, it is understood that the free concentration of lesinurad in the urinary lumen determines the efficacy. The presentation will examine the pharmacokinetic properties that govern the pharmacodynamic activity of lesinurad by using modeling and simulation to understand proximal tubule concentrations.