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

Jeroen Koomen, Jasper Stevens, George Bakris, Ricardo Correa-Rotter, Fan Fan Hou, Dalane W. Kitzman, Donald Kohan, Hirofumi Makino, John J. McMurray, Hans-Henrik Parving, Vlado Perkovic, Sheldon W. Tobe, Dick de Zeeuw, Hiddo J. L. Heerspink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
24 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)561-568
Number of pages8
JournalDiabetes obesity & metabolism
Issue number2
DOIs
Publication statusPublished - Feb-2021

Keywords

  • atrasentan
  • diabetic kidney disease
  • endothelin receptor antagonist
  • pharmacodynamics
  • randomized controlled trial
  • ENDOTHELIN
  • ALBUMINURIA

Cite this