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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.

ABSTRACT: 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.

SUBMITTER: Jaisser F

PROVIDER: S-EPMC8264204 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesOcedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of ocedurenone in individuals with moderate hepatic impairment.MethodsThis study was an open-label, nonrandomized, multi-center study investigating the pharmacokinetics, safety, and tolerability of a single dose of 0.5 mg ocedurenone administered orally in male and female subjects with moderate hepatic impairment (Child-Pugh B, score 7-9) compared with subjects with normal hepatic function. Serial blood samples were obtained from predose through 264 h postdose for analysis of ocedurenone concentrations using a validated liquid chromatography-tandem mass spectrometry method. Free ocedurenone concentrations in plasma were determined ex vivo using equilibrium dialysis.ResultsFollowing a single oral dose of 0.5 mg ocedurenone administered to subjects with moderate hepatic impairment and subjects with normal hepatic function, ocedurenone was steadily absorbed with median time to peak drug concentration (Tmax) values of 4 and 3 h, respectively. After reaching maximum plasma concentration (Cmax), the disposition of ocedurenone appeared to be biphasic. The geometric mean t1/2 values for the moderate hepatic impairment group and normal hepatic function group were 75.6 and 65.7 h, respectively. Ocedurenone systemic exposure, as assessed by area under the plasma concentration-time curve (AUC) was 23.5-26.6% lower in subjects with moderate hepatic impairment versus subjects with normal hepatic function, whereas Cmax was 41.2% lower. Ocedurenone was determined to be > 99.7% bound to total protein in plasma. Hepatic impairment appeared not to change plasma protein binding or the unbound free fraction. Ocedurenone was safe and well-tolerated in all participants.ConclusionsConsidering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and Cmax do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. CLINICAL TRIAL IDENTIFIER ( WWW.ClinicaltrialsGOV ): NCT04534699.

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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.

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