In vitro and in vivo preclinical pharmacokinetic characterization of aficamten, a small molecule cardiac myosin inhibitor

• Published in: Xenobiotica p. 1
• Main Authors: Sukhun, Rajaa, Cremin, Peadar, Xu, Donghong, Zamora, Jeanelle, Cheung, Jennifer, Ashcraft, Luke, Grillo, Mark P, Morgan, Bradley P
• Format: Journal Article
• Language: English
• Published: England 09.08.2024
• Subjects: allometric scaling; Aficamten; human prediction; induction; transporters; pharmacokinetics; cardiac myosin inhibitor; CK-3773274; CYP inhibition; metabolite identification
• ISSN: 1366-5928
• DOI: 10.1080/00498254.2024.2389407

Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical and 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 in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamten 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 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.