PDF(Pubmed)
Abstract：
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, Cmax was reached within a median Tmax 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.
摘要：
阻塞性肥厚型心肌病（oHCM）是HCM的一种亚型，其特征是由心肌肥大和二尖瓣和器官的解剖改变引起的左心室流出道阻塞。Mavacamten,一种心脏肌球蛋白抑制剂，主要由CYP2C19在肝脏中代谢，是第一种也是唯一一种被批准用于治疗有症状的纽约心脏协会（NYHA）II-III类oHCM的靶向药物。以前的药代动力学（PK）的mavacamten的健康白种人的结果，日本人,亚洲参与者证明，mavacamten暴露受CYP2C19代谢状态的影响。这个开放标签，平行组，I期试验旨在确定具有不同CYP2C19基因型的健康中国参与者中mavacampen的PK和安全性。主要结果是确定健康中国参与者中mavacamten的PK；次要结果是检查安全性和耐受性。在禁食的健康成年中国人单次口服15或25毫克mavacamten后，Cmax在0.6-1.5h的中值Tmax内达到，表明吸收迅速。个体差异中等，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增加的总暴露量。CYP2C19基因型分层后，与之前的PK研究相比,不同种族群体的mavacamten总暴露量相似.在这项研究中没有观察到显著的不良事件。在所有CYP2C19基因型中，单次口服15mg的mavacamten具有良好的耐受性，25mg剂量在CYP2C19基因型UM/RM/NM的健康参与者中耐受性良好。中国健康人群中mavacampen的PK谱与其他健康人群一致。
