Abstract 10732: BAY 94-8862 Exerts a Potent Natriuretic Effect in Healthy Male Subjects Pre-treated With Fludrocortisone: Findings From a Proof-of-concept Study
Background Activation of the mineralocorticoid receptor (MR) by aldosterone is known to promote the retention of sodium by the kidney and has an important role in the pathophysiology of heart failure. BAY 94-8862 is a novel non-steroidal MR antagonist that has been shown to competitively inhibit the action of aldosterone in vitro with superior selectivity and potency compared with currently marketed MR antagonists.
Purpose To investigate the effect of BAY 94-8862 on natriuresis in healthy male volunteers after administration of fludrocortisone, a MR agonist.
Method In a combined crossover and group-comparison dose-escalation study, volunteers were randomized to receive single oral doses of BAY 94-8862 (2.5-20 mg polyethylene glycol [PEG] solution, or 2 × 10 mg immediate release [IR] tablets), placebo or eplerenone 50 mg. All received fludrocortisone 0.5 mg 2 h before administration of study drug. Adverse events, blood pressure, heart rate, neurohormone levels, mRNA and urine electrolytes were evaluated at baseline and at regular intervals post study drug administration.
Results Overall, 68 healthy male volunteers were enrolled into the study and randomized: 58 were valid for pharmacodynamic analysis (mean age, 35.8 years; mean body mass index, 24.6 kg/m2). All single oral doses of BAY 94-8862 were well tolerated and did not influence blood pressure, heart rate, neurohormone levels or mRNA. As expected, fludrocortisone 0.5 mg decreased urinary sodium/potassium (Na/K)-ratio in individuals receiving placebo. This effect was reversed by administration of BAY 94-8862 or eplerenone. BAY 94-8862 exerted a dose-dependent natriuretic effect compared with placebo at all doses studied. When administered as 20 mg PEG solution or 2 x 10 IR tablets, BAY 94-8862 increased Na/K-ratio significantly compared with eplerenone 50 mg (p = 0.0077 and p = 0.0028, respectively, in the 2-10 h interval after drug administration). By contrast, eplerenone 50 mg was typically more effective in increasing Na/K-ratio than BAY 94-8862 at doses below 10 mg.
Conclusions BAY 94-8862 exerts a dose-dependent natriuretic effect in healthy male volunteers pre-treated with fludrocortisone. Furthermore, BAY 94-8862 is more effective than eplerenone 50 mg when administered at a dose of 20 mg.
- © 2012 by American Heart Association, Inc.