The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury
The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-...
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doaj-70307f2212d94cf0ada186684e06954e2021-06-24T05:27:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-06-011210.3389/fphar.2021.604928604928The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal InjuryFrédéric Jaisser0Xiaojuan Tan1Shuangshuang Chi2Jinrong Liu3Ping Wang4Mark Bush5Vincent Benn6Y. Fred Yang7Jay Zhang8INSERM UMRS1138, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers, Paris, FranceKBP BioSciences Co., Ltd., Shandong, ChinaKBP BioSciences Co., Ltd., Shandong, ChinaKBP BioSciences Co., Ltd., Shandong, ChinaKBP BioSciences Co., Ltd., Shandong, ChinaNuventra Inc., Durham, NC, United StatesKBP BioSciences USA Inc., Princeton, NJ, United StatesKBP BioSciences USA Inc., Princeton, NJ, United StatesKBP BioSciences USA Inc., Princeton, NJ, United StatesThe therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.https://www.frontiersin.org/articles/10.3389/fphar.2021.604928/fullmineralocorticoid receptorurinary albumin to creatinine ratioUACRhyperkalemiatherapeutic indexnephropathy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Frédéric Jaisser Xiaojuan Tan Shuangshuang Chi Jinrong Liu Ping Wang Mark Bush Vincent Benn Y. Fred Yang Jay Zhang |
spellingShingle |
Frédéric Jaisser Xiaojuan Tan Shuangshuang Chi Jinrong Liu Ping Wang Mark Bush Vincent Benn Y. Fred Yang Jay Zhang The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury Frontiers in Pharmacology mineralocorticoid receptor urinary albumin to creatinine ratio UACR hyperkalemia therapeutic index nephropathy |
author_facet |
Frédéric Jaisser Xiaojuan Tan Shuangshuang Chi Jinrong Liu Ping Wang Mark Bush Vincent Benn Y. Fred Yang Jay Zhang |
author_sort |
Frédéric Jaisser |
title |
The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury |
title_short |
The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury |
title_full |
The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury |
title_fullStr |
The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury |
title_full_unstemmed |
The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury |
title_sort |
non-steroidal mineralocorticoid receptor antagonist kbp-5074 limits albuminuria and has improved therapeutic index compared with eplerenone in a rat model with mineralocorticoid-induced renal injury |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2021-06-01 |
description |
The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window. |
topic |
mineralocorticoid receptor urinary albumin to creatinine ratio UACR hyperkalemia therapeutic index nephropathy |
url |
https://www.frontiersin.org/articles/10.3389/fphar.2021.604928/full |
work_keys_str_mv |
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