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Br J Clin Pharmacol. 2018 Aug;84(8):1821-1829. doi: 10.1111/bcp.13616. Epub 2018 Jun 7.

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

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Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Osaka Pharmacology Clinical Research Hospital, Osaka, Japan.
Daiichi Sankyo, Inc., New Jersey, USA.



To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men.


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.


In total, 48/48 and 39/40 subjects completed the single- and multiple-dose studies, respectively. Exposures were generally dose-proportional. The tmax , t1/2 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). Vz /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.


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.


esaxerenone; mineralocorticoid receptor antagonist; pharmacodynamics; pharmacokinetics; phase I; safety

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