@article{98b074bc95614eb8afe3e2f5cb6fdb67,
title = "Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease",
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.",
author = "Koomen, {Jeroen V.} and Jasper Stevens and George Bakris and Ricardo Correa-Rotter and Hou, {Fan Fan} and Kitzman, {Dalane W.} and Kohan, {Donald E.} and Hirofumi Makino and McMurray, {John J.V.} and Parving, {Hans Henrik} and Vlado Perkovic and Tobe, {Sheldon W.} and {de Zeeuw}, Dick and Heerspink, {Hiddo J.L.}",
note = "Funding Information: H.J.L.H. is consultant to AbbVie, AstraZeneca, Boehringer Ingelheim, Bayer, Chinook, CSL Behring, Gilead, Janssen, Merck, Mundipharma, Mitsubishi Tanabe, Novo Nordisk, and Retrophin. He received research support from AstraZeneca, AbbVie, Boehringer Ingelheim, and Janssen. D.E.K. is a consultant to AbbVie, Chinook, Janssen, and Retrophin. G.B. is a consultant for Bayer, Relypsa, Janssen, Merck, and Vascular Dynamics. R.C.‐R. serves on advisory boards for Boehringer and AstraZeneca and has been a speaker for AstraZeneca, Boehringer Ingelheim, AbbVie, Takeda, Amgen, and Janssen; he is consultant for AstraZeneca, Novonordisk, Janssen, and Boehringer Ingelheim. He received research support from AstraZeneca, AbbVie, and GlaxoSmithKline. F.F.H. is a consultant for and received honoraria from AbbVie and AstraZeneca. D.W.K. received grant funding from Bayer, Novartis, and the National Institutes of Health, and has been a consultant for AbbVie, Bayer, Merck, Boehringer Ingelheim, Corvia, CinRx, GlaxoSmithKline, Duke Clinical Research Institute, St Luke{\textquoteright}s Medical Center, and AstraZeneca. H.M. is a consultant for AbbVie, Boehringer‐Ingelheim, and Teijin Pharma. V.P. has served on Steering Committees for trials funded by AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novo Nordisk, Retrophin, and Tricida; and has participated in scientific presentations or advisory boards with AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol‐Myers Squibb, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, and Tricida. S.W.T. participates on a steering committee for Bayer Fidelio/Figaro studies, and speaker{\textquoteright}s bureau with Servier and Pfizer. D.d.Z. serves on advisory boards or is a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi Tanabe; participates in steering committees or is a speaker for AbbVie and Janssen; and is on the data safety and monitoring committees for Bayer. H.‐H.P. serves as a consultant for AbbVie. All other authors declared no competing interests for this work. Funding Information: J.S. is supported by a grant from the Novo Nordisk Foundation, Grant Number NNF OC0013659. H.J.L.H. is supported by a VIDI grant from the Netherlands Organisation for Scientific Research (917.15.306). The SONAR trial was funded by Abbvie. Publisher Copyright: {\textcopyright} 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.",
year = "2021",
month = jun,
doi = "10.1002/cpt.2143",
language = "English",
volume = "109",
pages = "1631--1638",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "6",
}
