First‐in‐human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor

Autor: Hidetoshi Shimizu, Michael A. Tortorici, Yoshiyasu Ohta, Kei Ogawa, Sheikh Mohammed Ashfaq Rahman, Aya Fujii, Yuki Hiraga, Mizue Kawai, Kanami Sugimoto‐Kawabata, Mattheus (Thijs) vanIersel, Jan Jaap vanLier, Stephen Djedjos, B. T. Slingsby, David M. Rodman
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Clinical and Translational Science, Vol 17, Iss 8, Pp n/a-n/a (2024)
Druh dokumentu: article
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.70000
Popis: Abstract Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β‐hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone‐dependent, uncontrolled hypertension, including treatment‐resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374‐fold selectivity for CYP11B2 vs. CYP11B1. A first‐in‐human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single‐ and multiple‐dose administration, lorundrostat plasma levels peaked 1–3 h after administration with a t1/2 of 10–12 h. Plasma aldosterone decreased up to 40% with single 100‐mg to 200‐mg doses and up to 70% with single 400 to 800‐mg doses. Plasma aldosterone returned to baseline within 16 h after single 100‐mg doses and multiple once‐daily 120‐mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose‐ and exposure‐dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin‐stimulated cortisol production and only a modest increase in mean serum potassium.
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