Back to Search
Start Over
Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor, Developed for Patients With Heart Failure With Preserved Ejection Fraction.
- Source :
-
Clinical and translational science [Clin Transl Sci] 2021 May; Vol. 14 (3), pp. 812-819. Date of Electronic Publication: 2021 May 02. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2020 AstraZeneca. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Administration, Oral
Adult
Dose-Response Relationship, Drug
Double-Blind Method
Healthy Volunteers
Humans
Male
Middle Aged
Pyrimidines administration & dosage
Pyrimidines pharmacokinetics
Pyrroles administration & dosage
Pyrroles pharmacokinetics
Single-Blind Method
Stroke Volume
Ventricular Function, Left
Young Adult
Heart Failure drug therapy
Peroxidase antagonists & inhibitors
Pyrimidines adverse effects
Pyrroles adverse effects
Subjects
Details
- Language :
- English
- ISSN :
- 1752-8062
- Volume :
- 14
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical and translational science
- Publication Type :
- Academic Journal
- Accession number :
- 32770730
- Full Text :
- https://doi.org/10.1111/cts.12859