Single‐ and multiple‐dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects

Aims To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men. Methods Double‐blind, placebo‐controlled, sequential, dose‐escalation studies were conducted in subjects randomized to receive oral once‐daily esaxerenone (ranges: 5–200 mg [single‐dose]; 10–100 mg over 10 days [multiple‐dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph–tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated. Results In total, 48/48 and 39/40 subjects completed the single‐ and multiple‐dose studies, respectively. Exposures were generally dose‐proportional. The t max , t 1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5–4.0 h, 22.3–25.1 h, and 4.0–5.2 l h –1 (multiple‐dose study). V z /F ranged from 136.5 to 283.7 l in the multiple‐dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36–1.98. The urinary Na + /K + ratio increased after single‐dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose‐dependently. Although blood potassium levels increased dose‐dependently in the multiple‐dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l –1 in the 100‐mg group), no safety/tolerability‐related problems were detected in either study. Conclusions Exposure levels in healthy adults receiving esaxerenone were generally dose‐proportional. Dose‐dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple‐dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.