Affiliation:
1. Division of Internal Medicine and Hypertension University of Torino Torino Italy
2. Clinic for Nephrology and Hypertension, Inselspital, Bern University Hospital University of Bern Bern Switzerland
3. DAMIAN Pharma AG Walchwil Switzerland
4. Covance Clinical Research Leeds UK
5. Faculty of Biology and Medicine Lausanne University Lausanne Switzerland
Abstract
AimsHigh 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.MethodsThis 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.ResultsDP13 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).ConclusionsIn 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.
Subject
Pharmacology (medical),Pharmacology
Cited by
2 articles.
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