Amgen, Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
Covance Inc., Madison, WI, USA.
Clin Pharmacokinet. 2021 Aug;60(8):1041-1048. doi: 10.1007/s40262-021-01014-0. Epub 2021 Mar 26.
Omecamtiv mecarbil is a novel selective cardiac myosin activator (myotrope) under investigation for the treatment of heart failure with reduced ejection fraction. The objective of this clinical study was to estimate the effect of varying degrees of renal impairment on the pharmacokinetics of omecamtiv mecarbil single dose (50 mg) under fasted conditions.
This phase I, open-label, non-randomized, parallel-group study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of omecamtiv mecarbil 50 mg in individuals with normal renal function or mild, moderate, and severe renal impairment, including end-stage renal disease requiring dialysis. Geometric least-squares mean ratios of maximum observed concentration (C) and area under the plasma concentration-time curve (AUC) and 90% confidence intervals were derived for comparisons of renal impairment vs normal renal function. Participants were monitored for adverse events.
Thirty-one participants received treatment and completed the study. Geometric mean exposures were similar for participants with renal impairment (AUC range, 2550-3220 hng/mL; C range, 78.9-107 ng/mL) and participants with normal renal function (AUC, 2790 hng/mL; C, 92.6 ng/mL), with geometric least-squares mean ratios of 85.2-125.9. Exposure was similar on dialysis vs non-dialysis days in participants with end-stage renal disease (AUC, 1650 vs 1700 h*ng/mL; C, 100.0 vs 107.0 ng/mL). Four participants (12.9%) reported four treatment-emergent adverse events. No deaths, treatment-emergent adverse events leading to discontinuation, or serious adverse events occurred.
Omecamtiv mecarbil pharmacokinetics were not meaningfully affected by renal function or hemodialysis, suggesting the same dosing strategy can be used in individuals with normal renal function or renal impairment. Oral administration of omecamtiv mecarbil was not associated with major tolerability findings. This study supports omecamtiv mecarbil for the treatment of heart failure in individuals with or without renal impairment.
Omecamtiv mecarbil 是一种新型选择性心肌肌球蛋白激活剂（肌动蛋白），目前正在研究用于治疗射血分数降低的心力衰竭。本临床研究的目的是评估不同程度的肾功能损害对禁食条件下 omecamtiv mecarbil 单剂量（50mg）药代动力学的影响。
这项 I 期、开放标签、非随机、平行组研究评估了 omecamtiv mecarbil 50mg 单口服剂量在肾功能正常或轻度、中度和重度肾功能损害个体（包括需要透析的终末期肾病）中的药代动力学、安全性和耐受性。对于肾功能损害与肾功能正常的比较，推导了最大观测浓度（C）和血浆浓度-时间曲线下面积（AUC）的几何均数比值及其 90%置信区间。监测参与者的不良事件。
31 名参与者接受了治疗并完成了研究。肾功能损害者（AUC 范围 2550-3220hng/mL；C 范围 78.9-107ng/mL）和肾功能正常者（AUC 2790hng/mL；C 92.6ng/mL）的几何均数暴露相似，几何均数比值为 85.2-125.9。在终末期肾病患者中，透析日和非透析日的暴露情况相似（AUC 1650 与 1700h*ng/mL；C 100.0 与 107.0ng/mL）。四名参与者（12.9%）报告了四起治疗后出现的不良事件。无死亡、治疗后出现的不良事件导致停药或严重不良事件发生。
肾功能或血液透析对 omecamtiv mecarbil 的药代动力学无明显影响，提示肾功能正常或肾功能损害的个体可采用相同的给药方案。口服 omecamtiv mecarbil 与主要耐受性发现无关。这项研究支持 omecamtiv mecarbil 用于治疗有或无肾功能损害的心力衰竭患者。
