Inter-individual variability in atrasentan exposure partly explains variability in kidney protection and fluid retention responses: a post hoc analysis of the SONAR trial

Koomen, J. V. et al. (2021) Inter-individual variability in atrasentan exposure partly explains variability in kidney protection and fluid retention responses: a post hoc analysis of the SONAR trial. Diabetes, Obesity and Metabolism, 23(2), pp. 561-568. (doi: 10.1111/dom.14252) (PMID:33184931) (PMCID:PMC7839558)

Abstract

Aim: To evaluate whether atrasentan plasma exposure explains between-patient variability in urinary albumin-to-creatinine ratio (UACR) response, a surrogate for kidney protection, and B-type natriuretic peptide (BNP) response, a surrogate for fluid expansion. Methods: Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run-in period. Individual area under the concentration-time-curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. Results: The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th-97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was −36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th-97.5th P: −76.2% to 44.5%; BNP, 2.5th-97.5th P: −71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P < .01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P < .01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). Conclusion: Atrasentan plasma exposure varied among individual patients and partially explained between-patient variability in efficacy and safety response.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McMurray, Professor John
• Authors: Koomen, J. V., Stevens, J., Bakris, G., Correa‐Rotter, R., Hou, F. F., Kitzman, D. W., Kohan, D., Makino, H., McMurray, J. J. V., Parving, H.‐H., Perkovic, V., Tobe, S. W., de Zeeuw, D., and Heerspink, H. J.L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Diabetes, Obesity and Metabolism
• Publisher: Wiley
• ISSN: 1462-8902
• ISSN (Online): 1463-1326
• Published Online: 12 November 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Diabetes, Obesity and Metabolism 23(2): 561-568
• Publisher Policy: Reproduced under a Creative Commons License