In vitro and in vivo preclinical pharmacokinetic characterization of aficamten, a small molecule cardiac myosin inhibitor
Creators: name: Sukhun, Rajaa
name: Cremin, Peadar
name: Xu, Donghong
name: Zamora, Jeanelle
name: Cheung, Jennifer
name: Ashcraft, Luke
name: Grillo, Mark P.
name: Morgan, Bradley P.
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Cell Biology
subject: Physiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Biological Sciences not elsewhere classified
subject: Developmental Biology
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology
subject: Computational Biology

description: Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical <i>in vitro</i> and <i>in vivo</i> studies.Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stability <i>in vitro</i> in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamten <i>in vivo</i> clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse.Aficamten was metabolised <i>in vitro</i> to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten.Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing ‘rule-of-exponents’. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1.No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten. Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical <i>in vitro</i> and <i>in vivo</i> studies. Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stability <i>in vitro</i> in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers. Aficamten <i>in vivo</i> clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse. Aficamten was metabolised <i>in vitro</i> to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten. Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing ‘rule-of-exponents’. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1. No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten.