CYP11B2 Inhibitor Dexfadrostat Phosphate Suppresses the Aldosterone-to-Renin Ratio, an Indicator of Sodium Retention, in Healthy Volunteers.

Mulatero, Paolo; Groessl, Michael; Vogt, Bruno; Schumacher, Christoph; Steele, Ronald Edward; Brooks, Ashley; Hossack, Stuart; Brunner, Hans-Rudolf (2023). CYP11B2 Inhibitor Dexfadrostat Phosphate Suppresses the Aldosterone-to-Renin Ratio, an Indicator of Sodium Retention, in Healthy Volunteers. British journal of clinical pharmacology, 89(8), pp. 2483-2496. Wiley-Blackwell 10.1111/bcp.15713

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AIM

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 mg, 8 mg 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 mg, 8 mg, 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-hour aldosterone suppression after 8 days of treatment, unlike the 8 mg 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension

UniBE Contributor:

Grössl, Michael, Vogt, Bruno

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0306-5251

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Pubmed Import

Date Deposited:

15 Mar 2023 08:36

Last Modified:

20 Jul 2023 00:13

Publisher DOI:

10.1111/bcp.15713

PubMed ID:

36914591

Uncontrolled Keywords:

Aldosterone CYP11B2 aldosterone synthase inhibition aldosterone-to-renin ratio healthy volunteers renin sodium/potassium balance

URI:

https://boris.unibe.ch/id/eprint/180103

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