Wu Xiaojie, Chen Nanye, Hsu Peiwen, Sun Jing, Li Wenting, Wang Qi, Samira Merali, Wei Qiong, Yu Jicheng, Cao Guoying, Yang Haijing, Wang Lili, Wang Jingjing, Jin Yi, Liu Wei, Wu Jufang, He Jinjie, Lyu Cheng, Zhang Jing
Phase 1 Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China.
National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
Clin Transl Sci. 2024 Jul;17(7):e13877. doi: 10.1111/cts.13877.
Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II-III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open-label, parallel-group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, C was reached within a median T of 0.6-1.5 h, indicating rapid absorption. Inter-individual variability was moderate, and individuals carrying non-functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half-life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.
梗阻性肥厚型心肌病（oHCM）是肥厚型心肌病的一种亚型，其特征是由于心肌肥厚以及二尖瓣及其附属结构的解剖改变导致左心室流出道梗阻。马伐卡坦是一种主要在肝脏中由CYP2C19代谢的心肌肌球蛋白抑制剂，是首个也是唯一获批用于治疗有症状的纽约心脏协会（NYHA）II-III级oHCM的靶向药物。此前马伐卡坦在健康白种人、日本人和亚洲参与者中的药代动力学（PK）结果表明，马伐卡坦的暴露量受CYP2C19代谢状态的影响。这项开放标签、平行组、I期试验旨在确定马伐卡坦在具有不同CYP2C19基因型的健康中国参与者中的PK及安全性。主要结局是确定马伐卡坦在健康中国参与者中的PK；次要结局是检查安全性和耐受性。在空腹的健康成年中国个体中单次口服15或25毫克马伐卡坦后，在0.6 - 1.5小时的中位达峰时间（T）内达到峰浓度（C），表明吸收迅速。个体间变异性中等，携带无功能CYP2C19等位基因（*2/*2、*3/3或2/*3）的个体表现出更长的半衰期和更高的总暴露量。在对CYP2C19基因型进行分层后，与之前的PK研究相比，不同种族群体中马伐卡坦的总暴露量相似。本研究中未观察到显著不良事件。在所有CYP2C19基因型中，单次口服15毫克马伐卡坦耐受性良好，25毫克剂量在CYP2C19基因型为超快速代谢/快速代谢/正常代谢（UM/RM/NM）的健康参与者中耐受性良好。马伐卡坦在健康中国人群中的PK特征与其他健康人群一致。
