Xu Donghong, Lutz Justin D, Divanji Punag, Li Jianlin, Benattia Youcef, Griffith Adrienne, Heitner Stephen B, Kupfer Stuart, German Polina
Department of Clinical Pharmacology, Cytokinetics, Incorporated, 350 Oyster Point Blvd, South San Francisco, CA, 94080, USA.
Department of Clinical Research, Cytokinetics, Incorporated, South San Francisco, CA, USA.
Clin Pharmacokinet. 2025 Mar;64(3):397-406. doi: 10.1007/s40262-025-01481-9. Epub 2025 Feb 5.
Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment.
The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM.
Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function.
No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.
阿非卡胺是一种小分子选择性心肌肌球蛋白抑制剂，正在研发用于治疗有症状的梗阻性肥厚型心肌病（oHCM）。阿非卡胺主要通过肝脏代谢消除，肾脏排泄起次要作用。本研究的目的是评估阿非卡胺在中度肝功能损害或轻度至中度肾功能损害患者中的药代动力学（PK），以为轻度或中度肝功能损害或轻度至中度肾功能损害的肥厚型心肌病患者提供给药建议。
在一项1期单剂量、开放标签、平行组研究中，评估了肝功能损害对单剂量20 mg阿非卡胺PK的影响，该研究纳入了中度（n = 8）肝功能损害（Child-Pugh B级）的健康参与者与肝功能正常的参与者（n = 8）。全程监测安全性。使用oHCM患者2/3期临床数据的群体药代动力学（PopPK）模型评估肾功能损害对阿非卡胺PK的影响。
中度肝功能损害参与者与肝功能正常参与者的阿非卡胺PK相似。未报告严重或严重的治疗中出现的不良事件或具有临床意义的实验室异常。轻度或中度肾功能损害的oHCM患者与肾功能正常患者的阿非卡胺暴露量无临床意义上的差异。
中度肝功能损害参与者未观察到阿非卡胺PK有临床相关变化。群体PK分析表明，轻度或中度肾功能损害对oHCM患者的阿非卡胺PK无统计学或临床显著影响。轻度或中度肝或肾功能损害患者可能无需调整阿非卡胺剂量。
