LY3045697: Results from two randomized clinical trials of a novel inhibitor of aldosterone synthase
| Autor: | Eyas Raddad, Joanne Sloan-Lancaster, James Voelker, Amy Flynt, Y. Jin, Jeffrey W. Miller |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Aldosterone synthase Medicine (General) medicine.medical_specialty Adolescent Hydrocortisone Aldosterone synthase inhibitor Cortodoxone cortisol 030204 cardiovascular system & hematology Pharmacology law.invention Young Adult 03 medical and health sciences chemistry.chemical_compound R5-920 0302 clinical medicine Endocrinology Mineralocorticoid receptor Randomized controlled trial law Internal medicine Internal Medicine Cytochrome P-450 CYP11B2 Humans Medicine Arterial Pressure mineralocorticoid receptor antagonists Enzyme Inhibitors Aged Demography aldosterone Aldosterone Dose-Response Relationship Drug biology business.industry LY3045697 Middle Aged 030104 developmental biology chemistry potassium regulation Potassium biology.protein Original Article Female business chronic kidney disease |
| Zdroj: | Journal of the Renin-Angiotensin-Aldosterone System, Vol 18 (2017) Journal of the Renin-Angiotensin-Aldosterone System: JRAAS |
| ISSN: | 1752-8976 1470-3203 |
| Popis: | Introduction:LY3045697 is a potent and selective aldosterone synthase (CYP11B2) inhibitor that was developed as a safer alternative to mineralocorticoid receptor antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well as potassium ion homeostasis, were evaluated in two clinical studies in healthy subjects.Materials and methods:Two incomplete, placebo-controlled crossover-design clinical studies examined safety, pharmacodynamics, and pharmacokinetics under single and repeated dose conditions in healthy subjects. Pharmacodynamics was assessed following oral potassium challenge and intravenous adrenocorticotropic hormone procedures with spironolactone 25 mg/d as an active comparator.Results:A total of 51 subjects participated in the two studies, which included 38 males and 13 females (of non-childbearing potential), from 18–65 years old. LY3045697 caused rapid dose and concentration-dependent unstimulated plasma aldosterone concentration reduction seen as early as 4 h after the first dose at dose levels as low as 1 mg, and reaching near complete suppression at high doses. The potency (IC50) decreased significantly upon multiple dosing. After eight days of dosing, post-adrenocorticotropic hormone challenge plasma aldosterone concentration increase was dose-dependently blunted by LY3045697 with high potency with a dose as low as 0.1 mg resulting in substantial effect, and with an overall IC50of 0.38 ng/ml. Minor reductions in cortisol were observed only at the top dose of 300 mg. LY3045697 is generally safe and tolerated, and exhibits linear pharmacokinetics.Conclusions:LY3045697 is a potent and highly selective aldosterone synthase inhibitor with selectivity for CYP11B2, offering a substantial potential advantage over previous aldosterone synthase inhibitors evaluated in the clinic. |
| Databáze: | OpenAIRE |
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