Preclinical in vitro and in vivo pharmacokinetic properties of danicamtiv, a new targeted myosin activator for the treatment of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a disease of the myocardium defined by left ventricular enlargement and systolic dysfunction leading to heart failure. Danicamtiv, a new targeted myosin activator designed for the treatment of DCM, was characterised in in vitro and in vivo preclinical studies. Danicam...

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Bibliographic Details
Published in:Xenobiotica 2021-02, Vol.51 (2), p.222-238
Main Authors: Grillo, Mark P., Markova, Svetlana, Evanchik, Marc, Trellu, Marc, Moliner, Patricia, Brun, Priscilla, Perreard-Dumaine, Anne, Vicat, Pascale, Yang, Chun, Driscoll, James P., Carlson, Tim J.
Format: Article
Language:English
Subjects:
allometric scaling
Animals
Biological Availability
Caco-2 Cells
Cardiac myosin activator
Cardiomyopathy, Dilated - drug therapy
danicamtiv
Dogs
Hepatocytes
human prediction
Humans
Male
metabolites
Mice
Microsomes, Liver
MYK-491
Myosins
pharmacokinetics
Protein Binding
Rats
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Summary:Dilated cardiomyopathy (DCM) is a disease of the myocardium defined by left ventricular enlargement and systolic dysfunction leading to heart failure. Danicamtiv, a new targeted myosin activator designed for the treatment of DCM, was characterised in in vitro and in vivo preclinical studies. Danicamtiv human hepatic clearance was predicted to be 0.5 mL/min/kg from in vitro metabolic stability studies in human hepatocytes. For human, plasma protein binding was moderate with a fraction unbound of 0.16, whole blood-to-plasma partitioning ratio was 0.8, and danicamtiv showed high permeability and no efflux in a Caco-2 cell line. Danicamtiv metabolism pathways in vitro included CYP-mediated amide-cleavage, N-demethylation, as well as isoxazole- and piperidine-ring-opening. Danicamtiv clearance in vivo was low across species with 15.5, 15.3, 1.6, and 5.7 mL/min/kg in mouse, rat, dog, and monkey, respectively. Volume of distribution ranged from 0.24 L/kg in mouse to 1.7 L/kg in rat. Oral bioavailability ranged from 26% in mouse to 108% in dog. Simple allometric scaling prediction of human plasma clearance, volume of distribution, and half-life was 0.64 mL/min/kg, 0.98 L/kg, and 17.7 h, respectively. Danicamtiv preclinical attributes and predicted human pharmacokinetics supported advancement toward clinical development.
ISSN:0049-8254
1366-5928
DOI:10.1080/00498254.2020.1839982