Wu Xiaojie, Puli Shilpa, Chen Nanye, Tian Zhuang, Hsu Peiwen, Sun Jing, Lyu Cheng, Merali Samira, Zhang Jing
Huashan Hospital, Fudan University, Shanghai, China.
Bristol Myers Squibb, Princeton, New Jersey, USA.
CPT Pharmacometrics Syst Pharmacol. 2025 Apr;14(4):751-758. doi: 10.1002/psp4.13312. Epub 2025 Jan 28.
Mavacamten is a cardiac myosin inhibitor for adults with obstructive hypertrophic cardiomyopathy (HCM). Dose optimization is performed 4 weeks after starting mavacamten, guided by periodic echo measurements of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Previously, a population pharmacokinetic (PPK) model was developed and exposure-response (E-R) of VLVOTg (efficacy) and LVEF (safety) was used to identify the mavacamten titration regimen with the optimal benefit/risk ratio, now included in the US prescribing information. Mavacamten is metabolized primarily by cytochrome P450 2C19 (CYP2C19) (74%), a highly polymorphic enzyme. China has a higher prevalence of poor CYP2C19 metabolizer phenotype compared with the global population; therefore, a previous model was adapted to include Chinese patients with obstructive HCM to identify the optimal dosing regimen for this population. Data from a phase I (healthy Chinese volunteers) and a phase III (EXPLORER-CN, NCT05174416; Chinese patients with obstructive HCM) trial of mavacamten were added to the previous PPK and E-R models, and the observed VLVOTg and LVEF from EXPLORER-CN were successfully simulated. Next, five echocardiography-guided titration regimens (plus the EXPLORER-CN regimen) using representative or equal CYP2C19 phenotypes were simulated. The final simulated regimen recommended with an optimal benefit/risk profile across CYP2C19 phenotypes included: down-titration at Week 4 (if VLVOTg < 20 mmHg), restart at Week 12, and up-titration at Week 12 (for VLVOTg ≥ 30 mmHg and LVEF ≥ 55%), and every 12 weeks thereafter. This supports the previously recommended regimen for Chinese patients with obstructive HCM, now approved by the National Medicinal Products Administration.
马伐卡坦是一种用于治疗梗阻性肥厚型心肌病（HCM）成人患者的心肌肌球蛋白抑制剂。在开始使用马伐卡坦4周后进行剂量优化，以周期性超声心动图测量瓦尔萨尔瓦动作左心室流出道梯度（VLVOTg）和左心室射血分数（LVEF）为指导。此前，已开发出一个群体药代动力学（PPK）模型，并利用VLVOTg（疗效）和LVEF（安全性）的暴露-反应（E-R）来确定具有最佳效益/风险比的马伐卡坦滴定方案，该方案现已纳入美国处方信息中。马伐卡坦主要通过细胞色素P450 2C19（CYP2C19）代谢（74%），这是一种高度多态性的酶。与全球人群相比，中国CYP2C19代谢不良者表型的患病率更高；因此，对先前的模型进行了调整，纳入中国梗阻性HCM患者，以确定该人群的最佳给药方案。将马伐卡坦的一项I期试验（健康中国志愿者）和一项III期试验（EXPLORER-CN，NCT05174416；中国梗阻性HCM患者）的数据添加到先前的PPK和E-R模型中，并成功模拟了EXPLORER-CN中观察到的VLVOTg和LVEF。接下来，模拟了使用代表性或相等CYP2C19表型的五种超声心动图指导的滴定方案（加上EXPLORER-CN方案）。最终模拟的具有跨CYP2C19表型最佳效益/风险特征的方案包括：第4周减量（如果VLVOTg<20 mmHg），第12周重新开始，第12周增量（对于VLVOTg≥30 mmHg且LVEF≥55%），此后每12周一次。这支持了先前为中国梗阻性HCM患者推荐的方案，该方案现已获得国家药品监督管理局的批准。
