Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease

Clin Pharmacol Ther. 2021 Jun;109(6):1631-1638. doi: 10.1002/cpt.2143. Epub 2021 Jan 5.


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.

Trial registration: NCT01858532.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Area Under Curve
  • Atrasentan / adverse effects*
  • Atrasentan / blood
  • Atrasentan / pharmacokinetics
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Nephropathies / complications*
  • Double-Blind Method
  • Endothelin Receptor Antagonists
  • Female
  • Glomerular Filtration Rate
  • Heart Failure / complications
  • Heart Failure / prevention & control*
  • Humans
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / prevention & control*
  • Male
  • Middle Aged
  • Treatment Outcome


  • Endothelin Receptor Antagonists
  • Atrasentan

Associated data