First‐in‐Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BMS‐986308: A Renal Outer Medullary Potassium Channel Inhibitor

Abstract

In patients with heart failure (HF) who respond inadequately to loop diuretic therapy, BMS‐986308, an oral, selective, reversible renal outer medullary potassium channel (ROMK) inhibitor may represent an effective diuretic with a novel mechanism of action. We present data from the first‐in‐human study aimed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) following single ascending doses of BMS‐986308 in healthy adult participants. Forty healthy participants, aged from 20 to 55 years, and body mass index (BMI) from 19.8 to 31.6 kg/m2 were assigned to 1 of 5 dose cohorts (1, 3, 10, 30, and 100 mg) and randomized (6:2) to receive BMS‐986308 oral solution or matching placebo. Following administration, BMS‐986308 was rapidly absorbed with a median time to maximum concentration (Tmax) of 1.00 to 1.75 h and exhibiting a mean terminal half‐life (t1/2) of approximately 13 h. Dose proportionality was evident in BMS‐986308 area under the concentration‐time curve (AUC), while maximum concentration (Cmax) was slightly greater than dose‐proportional. We observed that urine output (or diuresis; mL) and urinary sodium excretion (or natriuresis; mmol) increased in a dose‐dependent manner, starting at a minimum pharmacologically active dose of 30 mg. The largest mean changes from baseline in diuresis and natriuresis occurred in both the 6‐ and −24 h post‐dose period following administration of 100 mg (1683.0 mL and 2055.3 mL, and 231.7 mmol and 213.7 mmol, respectively; ***P < 0.001). Overall, single‐dose BMS‐986308 was found to be safe, well‐tolerated, with an excellent PK profile, and substantial diuretic and natriuretic activity.