AbstractApararenone is a long‐acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single‐ and multiple‐dose apararenone were assessed in 3 phase 1 randomized, double‐blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single‐dose apararenone (3.75–640 mg) and multiple‐dose apararenone (10–40 mg/day on days 1–14, 320 mg loading dose on day 1 + 10 mg/day on days 2–14, or 40–320 mg loading dose on day 1 + 2.5–20 mg/day on days 2–14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single‐dose apararenone (5–320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single‐dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose‐proportional increase was observed in PK parameters over the apararenone dose range of 3.75–40 mg; at higher doses, a less than dose‐proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half‐life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted.