Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor, Developed for Patients With Heart Failure With Preserved Ejection Fraction
| Autor: | Eva-Lotte Lindstedt, Carl Amilon, Hans Ericsson, David Han, Maria Heijer, Carl Whatling, Karin Nelander, Li-Ming Gan, Erik Michaëlsson, Maria Lagerström-Fermér, Muir Russell, M Kjaer |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Administration Oral RM1-950 Pharmacology General Biochemistry Genetics and Molecular Biology Ventricular Function Left Article chemistry.chemical_compound Young Adult Pharmacokinetics Double-Blind Method Medicine Humans Pyrroles Single-Blind Method General Pharmacology Toxicology and Pharmaceutics Whole blood Peroxidase Heart Failure biology Dose-Response Relationship Drug business.industry General Neuroscience Research Zymosan Stroke Volume General Medicine Articles Middle Aged Healthy Volunteers Pyrimidines Tolerability chemistry Pharmacodynamics Myeloperoxidase biology.protein Therapeutics. Pharmacology Public aspects of medicine RA1-1270 business Heart failure with preserved ejection fraction Ex vivo |
| Zdroj: | Clinical and Translational Science, Vol 14, Iss 3, Pp 812-819 (2021) Clinical and Translational Science |
| ISSN: | 1752-8054 1752-8062 |
| Popis: | We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single-blind, placebo-controlled study, following once-daily multiple ascending dosing to steady-state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half-life of ~ 60 hours. A dose/concentration-effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady-state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration-dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction. |
| Databáze: | OpenAIRE |
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