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Abstract: PO2371

KBP-5074, a Nonsteroidal Mineralocorticoid Receptor Antagonist, Reduces Urine Albumin-to-Creatinine Ratio and the Risk of Hyperkalemia in an Animal Model of CKD

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Jaisser, Frederic, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Jinrong, Liu, Kbp Biosciences Co Ltd, Jinan, China
  • Chi, Shuangshuang, Kbp Biosciences Co Ltd, Jinan, China
  • Wang, Ping, Kbp Biosciences Co Ltd, Jinan, China
  • Tan, Judy, Kbp Biosciences Co Ltd, Jinan, China
  • Benn, Vincent, KBP Biosciences USA Inc, Princeton, New Jersey, United States
  • Yang, Y. Fred, KBP Biosciences USA Inc, Princeton, New Jersey, United States
  • Zhang, Jay, KBP Biosciences USA Inc, Princeton, New Jersey, United States

Group or Team Name

  • KBP Biosciences USA Inc
Background

KBP-5074 is a novel non-steroidal mineralocorticoid receptor antagonist (MRA) being developed for uncontrolled hypertension and advanced chronic kidney disease. The primary objective of this study was to evaluate KBP-5074 and eplerenone for renal protection against aldosterone-mediated renal disease in a uninephrectomized Sprague-Dawley (SD) rat model.

Methods

Uninephrectomized rats were maintained on a 6% high salt diet, and received aldosterone infusion for 27 days. Urinary albumin to creatinine ratio (UACR), urinary Na+/K+, and serum K+ were assessed following 14 and 27 days of treatment. Blood samples were collected on days 1 and 26 to determine PK profiles. PK/PD analyses were performed on urinary Na+/K+ ratio, UACR, and serum K+.

Results

KBP-5074 (1, 3, and 10 mg/kg/day) significantly reduced UACR by 77%, 96%, and 99% respectively on day 14, and 50%, 86% and 99% respectively on day 26 in a dose dependent manner, while eplerenone (100 and 900 mg/kg/day) reduced UACR by 40% and 99% respectively on day 26. PK/PD analysis of Urinary Na+/K+ ratio indicated that KBP-5074 was approximately 18-fold more efficacious than eplerenone. Analysis of UACR and serum K+ indicated that the EC50 for serum K+ increase and UACR reduction was 538 nM and 22.0 nM respectively for KBP-5074, and 666 nM and 1071 nM respectively for eplerenone, resulting in a therapeutic index (TI) against hyperkalemia of 24.24 for KBP-5074 vs 0.62 for eplerenone. Thus, the TI against hyperkalemia of KBP-5074 was 39-fold superior to that of eplerenone, suggesting that the non-steroidal MRA KBP-5074 may present an extended therapeutic window as compared to the steroidal MRA eplerenone.

Conclusion

KBP-5074 demonstrated a significant effect on UACR reduction with less risk for hyperkalemia compared to eplerenone in a rat model of nephropathy.

Funding

  • Commercial Support