Preclinical <i>in vitro</i> and <i>in vivo</i> pharmacokinetic properties of danicamtiv, a new targeted myosin activator for the treatment of dilated cardiomyopathy
Creators: name: Grillo, Mark P.
name: Markova, Svetlana
name: Evanchik, Marc
name: Trellu, Marc
name: Moliner, Patricia
name: Brun, Priscilla
name: Perreard-Dumaine, Anne
name: Vicat, Pascale
name: Driscoll, James P.
name: Carlson, Tim J.
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Physiology
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Developmental Biology
subject: Cancer
subject: Mental Health
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology

description: 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 <i>in vitro</i> and <i>in vivo</i> preclinical studies.Danicamtiv human hepatic clearance was predicted to be 0.5 mL/min/kg from <i>in vitro</i> 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 <i>in vitro</i> included CYP-mediated amide-cleavage, <i>N</i>-demethylation, as well as isoxazole- and piperidine-ring-opening.Danicamtiv clearance <i>in vivo</i> 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. 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 <i>in vitro</i> and <i>in vivo</i> preclinical studies. Danicamtiv human hepatic clearance was predicted to be 0.5 mL/min/kg from <i>in vitro</i> 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 <i>in vitro</i> included CYP-mediated amide-cleavage, <i>N</i>-demethylation, as well as isoxazole- and piperidine-ring-opening. Danicamtiv clearance <i>in vivo</i> 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.