Garcia M Iveth, Bhardwaj Bhavya, Dame Keri, Charwat Verena, Siemons Brian A, Goswami Ishan, Ismaiel Omnia A, Mistry Sabyasachy, Feaster Tromondae K, Healy Kevin E, Ribeiro Alexandre J S, Blinova Ksenia
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Department of Bioengineering, California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA.
J Cardiovasc Dev Dis. 2025 Jul 26;12(8):285. doi: 10.3390/jcdd12080285.
New approach methodologies (NAMs), including microphysiological systems (MPSs), can recapitulate structural and functional complexities of organs. Vanoxerine was reported to induce cardiac adverse events, including torsade de points (TdP), in a Phase III clinical trial. Despite earlier nonclinical animal models and Phase I-II clinical trials, events of QT prolongation or proarrhythmia were not observed. Here, we utilized cardiac NAMs to evaluate the functional consequences of vanoxerine treatment on human cardiac excitation-contraction coupling. The cardiac MPS used in this study was a microfabricated fluidic culture platform with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) capable of evaluating voltage, intracellular calcium handling, and contractility. Likewise, the hiPSC-CM comprehensive in vitro proarrhythmia assay (CiPA) was employed based on multielectrode array (MEA). Vanoxerine treatment delayed repolarization in a concentration-dependent manner and induced proarrhythmic events in both NAM platforms. The complex cardiac MPS displayed a frequency-dependent vanoxerine response such that EADs were eliminated at a faster pacing rate (1.5 Hz). Moreover, exposure analysis revealed a 99% vanoxerine loss in the cardiac MPS. TdP risk analysis demonstrated high to intermediate TdP risk at clinically relevant concentrations of vanoxerine and frequency-independent EAD events in the hiPSC-CM CiPA model. These findings demonstrate that nonclinical cardiac NAMs can recapitulate clinical outcomes, including detection of vanoxerine-induced delayed repolarization and proarrhythmic effects. Moreover, this work provides a foundation to evaluate the safety and efficacy of novel compounds to reduce the dependence on animal studies.
新方法学（NAMs），包括微生理系统（MPSs），能够概括器官的结构和功能复杂性。在一项III期临床试验中，据报道瓦诺西汀会诱发心脏不良事件，包括尖端扭转型室速（TdP）。尽管有早期的非临床动物模型以及I - II期临床试验，但未观察到QT间期延长或心律失常事件。在此，我们利用心脏NAMs来评估瓦诺西汀治疗对人类心脏兴奋 - 收缩偶联的功能影响。本研究中使用的心脏MPS是一个微制造的流体培养平台，带有能够评估电压、细胞内钙处理和收缩性的人诱导多能干细胞衍生心肌细胞（hiPSC - CMs）。同样，基于多电极阵列（MEA）采用了hiPSC - CM综合体外心律失常分析（CiPA）。瓦诺西汀治疗以浓度依赖性方式延迟复极化，并在两个NAM平台中诱发心律失常事件。复杂的心脏MPS显示出频率依赖性的瓦诺西汀反应，使得在更快的起搏频率（1.5 Hz）下消除了早期后除极（EADs）。此外，暴露分析显示心脏MPS中有99%的瓦诺西汀损失。TdP风险分析表明，在瓦诺西汀的临床相关浓度下，hiPSC - CM CiPA模型中存在高到中度的TdP风险以及频率无关的EAD事件。这些发现表明，非临床心脏NAMs能够概括临床结果，包括检测瓦诺西汀诱导的延迟复极化和心律失常作用。此外，这项工作为评估新型化合物的安全性和有效性提供了基础，以减少对动物研究的依赖。
