Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers.

Autor: Kanefendt F; Clinical Pharmacokinetics, BAYER AG, Wuppertal, Germany., Thuß U; Bioanalytics, BAYER AG, Wuppertal, Germany., Becka M; Research and Clinical Sciences Statistics, BAYER AG, Wuppertal, Germany., Boxnick S; CRS Clinical Research Services, Wuppertal GmbH, Wuppertal, Germany., Berse M; CRS Clinical Research Services, Berlin GmbH, Berlin, Germany., Schultz A; CRS Clinical Research Services, Mannheim GmbH, Mannheim, Germany., Otto C; Experimental Medicine Cardiovascular and Hematology, BAYER AG, Wuppertal, Germany.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2019 May; Vol. 8 (4), pp. 467-479. Date of Electronic Publication: 2018 Jun 07.
DOI: 10.1002/cpdd.579
Abstrakt: The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction.
(© 2018, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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