扩张型心肌病(DCM)是由左心室扩大和收缩功能障碍导致心力衰竭定义的心肌疾病。Danicamtiv,一种用于治疗DCM的新型靶向肌球蛋白激活剂,在体外和体内临床前研究中进行了表征。根据人肝细胞中的体外代谢稳定性研究,预计Danicamtiv人肝清除率为0.5mL/min/kg。对于人类来说,血浆蛋白结合中等,未结合分数为0.16,全血与血浆的分配比为0.8,danicamtiv在Caco-2细胞系中显示出高通透性且无外排。体外Danicamtiv代谢途径包括CYP介导的酰胺裂解,N-去甲基化,以及异恶唑和哌啶开环。Danicamtiv在小鼠体内的清除率在物种中很低,分别为15.5、15.3、1.6和5.7mL/min/kg,rat,狗,猴子,分别。分布体积范围为小鼠0.24L/kg至大鼠1.7L/kg。口服生物利用度范围从小鼠的26%到狗的108%。人类血浆清除率的简单异速缩放比例预测,分配量,半衰期为0.64mL/min/kg,0.98L/kg,和17.7小时,分别。Danicamtiv临床前属性和预测的人体药代动力学支持了临床开发的发展。
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.