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Abstract: PO1025

Association of Atrasentan Plasma Exposure with Variability in Responses in Proxies of Kidney Protection and Fluid Retention: A Post Hoc Analysis of the SONAR Trial

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Koomen, Jeroen, Department of clinical pharmacy and pharmacology, University of Groningen, University Medical Center Groningen,, Groningen, Netherlands
  • Stevens, Jasper, Department of clinical pharmacy and pharmacology, University of Groningen, University Medical Center Groningen,, Groningen, Netherlands
  • Parving, Hans-Henrik, Rigshospitalet, Kobenhavn, Denmark
  • de Zeeuw, Dick, Department of clinical pharmacy and pharmacology, University of Groningen, University Medical Center Groningen,, Groningen, Netherlands
  • L Heerspink, Hiddo Jan, Department of clinical pharmacy and pharmacology, University of Groningen, University Medical Center Groningen,, Groningen, Netherlands

Group or Team Name

  • on behalf of the SONAR steering committee
Background

Atrasentan reduced urinary albumin:creatinine ratio (UACR) and the risk of kidney failure in patients with type 2 diabetes and chronic kidney disease in the SONAR trial. However, in this high risk population, atrasentan was also associated with fluid retention in some patients. We evaluated whether plasma exposure to atrasentan could explain between-patient variability in UACR response, a surrogate for kidney protection, and in B-type natriuretic peptide (BNP), as a biomarker of fluid expansion.

Methods

All patients received 0.75 mg atrasentan for six weeks in the active run-in (enrichment) period. Individual area under the concentration time curve (AUC) was estimated using a population pharmacokinetic model. Subsequently, the association between atrasentan AUC as well as baseline clinical characteristics with UACR and BNP response was estimated with linear regression in univariable and multivariable analyses.

Results

The median atrasentan AUC was 43.8 ng.h/mL which varied considerably among patients [2.5th-97.5th percentiles: 12.6 to 197.5 ng.h/ml]. Median UACR change at the end of enrichment was -36% and BNP change was 8.7%, which also varied among patients [UACR; 2.5th-97.5th percentiles: -76.2 to 44.5%; BNP;-71.5 to 300.0%]. Atrasentan AUC, along with certain clinical characteristics at baseline such as age, eGFR, and hemoglobin, was independently associated with greater UACR reduction (β -7.0% per ng.h/ml AUC; p<0.01) and greater BNP increase (β 4.5% per ng.h/ml AUC; p<0.01) .

Conclusion

Atrasentan plasma exposure varied among individual patients and in addition to other patient characteristics, explained the between-patient variability in UACR and BNP response.

Funding

  • Commercial Support