In vitro and in vivo preclinical pharmacokinetic characterisation of ulacamten, a small molecule cardiac myosin inhibitor for the treatment of heart failure with preserved ejection fraction (HFpEF)

Ulacamten, a targeted cardiac myosin inhibitor designed for the treatment of heart failure with preserved ejection fraction (HFpEF), was characterized in in vitro and in vivo preclinical assays.Ulacamten human hepatic clearance was predicted to be 5.7 mL/min/kg from in vitro metabolic stability studies in human liver microsomes. For human, plasma protein binding was moderate at 58.5% bound, whole blood-to-plasma partitioning ratio was 0.93, and ulacamten showed high permeability and no significant efflux in a Caco-2 cell-line.Ulacamten clearance in vivo across species was low-to-moderate with 9.33, 37.3, 7.57, and 11.6 mL/min/kg in mouse, rat, dog, and monkey, respectively. Volume of distribution ranged from 4.23 L/kg in dog to 8.89 L/kg in monkey. Oral bioavailability ranged from 12.6% in mouse to 51.4% in monkey.The predominant ulacamten metabolic pathways in vitro included CYP-mediated deformylation (metabolite M1) and hydroxylation of the methyl group of the methylcyclohexyl moiety (metabolite M2).The predicted human pharmacokinetic parameters clearance (CL), steady-state volume of distribution, and half-life were 4.5 mL/min/kg, 5.8 L/kg, and 14.9-hours, respectively, determined from an average of multiple prediction methods.Ulacamten preclinical attributes and predicted human pharmacokinetic parameters allowed for its progression to clinical development.