학술논문
CYP11B2 inhibitor dexfadrostat phosphate suppresses the aldosterone‐to‐renin ratio, an indicator of sodium retention, in healthy volunteers.
Document Type
Article
Author
Source
Subject
*SODIUM
*ADRENOCORTICOTROPIC hormone
*ADRENAL insufficiency
*VOLUNTEERS
*VOLUNTEER service
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Language
ISSN
0306-5251
Abstract
Aims: High aldosterone is a key driver of hypertension and long‐term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants. Methods: This randomized, double‐blind, placebo‐controlled study was conducted in two parts. In part A, a single‐ascending dose escalation, 16 participants received oral DP13 1–16 mg. Part B was a multiple‐ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing. Results: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone‐to‐renin ratio (ARR). Endocrine counter‐regulation resulted in the 4 mg dose no longer sustaining 24‐h aldosterone suppression after 8 days of treatment, unlike the 8‐ and 16 mg doses. There was no evidence of drug‐induced adrenal insufficiency (ACTH stress challenge). Conclusions: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone‐dependent hypertension and primary aldosteronism. [ABSTRACT FROM AUTHOR]