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 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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalClinical Pharmacology and Therapeutics
DOIs
Publication statusAccepted/In press - 2020

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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