Exposure-response analysis of the efficacy and safety of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with or without diabetic kidney disease.

Background: Esaxerenone is a novel non-steroidal mineralocorticoid receptor blocker. Here, we assessed efficacy and safety exposure-response relationships of esaxerenone and its covariates and thereby justified the recommended dosage regimens, focusing on the safety benefits of up-titration regimen in patients at higher risk for increased serum potassium (sK).

Methods: The relationships between model-derived individual esaxerenone exposure and efficacy (blood pressure [BP]) and safety (increased sK) were evaluated using multivariate linear regression and Cox regression analyses, respectively, using data from 1453 hypertensive patients with or without diabetic kidney disease in five clinical studies.

Results: Exposure-efficacy analyses demonstrated that higher exposure was linearly associated with greater BP reduction over the investigated dose range. Exposure-safety analyses showed that higher exposure was associated with a higher risk of increased sK under a fixed-dosing regimen; higher baseline sK and lower baseline estimated glomerular filtration rate (eGFR) were influential covariates. Model-based simulations suggested that fewer occurrences of increased sK are expected under the up-titration regimen (from 1.25 to 5 mg) relative to the fixed-dosing regimen (5 mg) in patients with different combinations of these covariates.

Conclusions: The exposure-response analyses supported the esaxerenone recommended doses and the safety benefits of using the up-titration regimen.