Jeroen V Koomen, Jasper Stevens, George Bakris, Ricardo Correa-Rotter, Fan Fan Hou, Dalane W Kitzman, Donald E Kohan, Hirofumi Makino, John J V McMurray, Hans-Henrik Parving, Vlado Perkovic, Sheldon W Tobe, Dick de Zeeuw, Hiddo J L Heerspink
Journal: Clinical pharmacology and therapeutics 2021;109(6):1631-1638
PMID: 33338269
Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.
© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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