Individual atrasentan exposure is associated with long-term kidney and heart failure outcomes in patients with type 2 diabetes and chronic kidney disease

Jeroen V Koomen, Jasper Stevens, George Bakris, Ricardo Correa-Rotter, 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*

*Corresponding author for this work

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Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase 2 trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase 3 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 to placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% 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.

Original languageEnglish
Pages (from-to)1631-1638
Number of pages8
JournalClinical Pharmacology & Therapeutics
Issue number6
Early online date18-Dec-2020
Publication statusPublished - Jun-2021

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