Abstract

1. Dilated cardiomyopathy (DCM) is a disease of the myocardium defined by left ventricular enlargement and systolic dysfunction leading to heart failure.

2. Danicamtiv, a new targeted myosin activator designed for the treatment of DCM, was characterised in in vitro and in vivo preclinical studies.

3. 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.

4. Danicamtiv metabolism pathways in vitro included CYP-mediated amide-cleavage, N-demethylation, as well as isoxazole- and piperidine-ring-opening.

5. 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.

6. 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.

7. Danicamtiv preclinical attributes and predicted human pharmacokinetics supported advancement toward clinical development.

摘要

1. 扩张型心肌病（DCM）是一种由左心室扩大和收缩功能障碍导致的心力衰竭所定义的心肌病。

2. Danicamtiv是一种设计用于治疗DCM的新型靶向肌球蛋白活化剂，已在体外和体内临床前研究中进行了表征。

3. 根据人肝细胞的体外代谢稳定性研究，Danicamtiv人肝清除率预计为0.5 mL / min / kg 。对于人而言，血浆蛋白结合是中等的，未结合分数为0.16，全血与血浆的分配比为0.8，而danicamtiv在Caco-2细胞系中显示出高渗透性且没有外排。

4. 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的开环。

5. 跨物种的体内Danicamtiv清除率较低，分别在小鼠，大鼠，狗和猴中为15.5、15.3、1.6和5.7 mL / min / kg。分布体积范围从小鼠的0.24 L / kg到大鼠的1.7 L / kg。口服生物利用度范围从小鼠的26％到狗的108％。

6. 对人血浆清除率，分布体积和半衰期的简单异速伸缩定标预测分别为0.64 mL / min / kg，0.98 L / kg和17.7 h。

7. Danicamtiv的临床前属性和预测的人类药代动力学支持了临床开发的进展。