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

Journal: Clinical pharmacology and therapeutics 2021;109(6):1631-1638

PMID: 33338269

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.

© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Address: Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.; American Society of Hypertension Comprehensive Hypertension Center, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.; National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.; Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, China.; Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.; Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.; Okayama University, Okayama, Japan.; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.; Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.; Faculty of Health Science, Aarhus University, Aarhus, Denmark.; George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia.; Division of Nephrology, Sunnybrook Health Sciences Centre, University of Toronto and the Northern Ontario School of Medicine, Toronto, Ontario, Canada.; Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.; George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia.
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