Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration-QTc Relationships
Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration-QTc Relationships
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DOI：
10.1002/cpt.1259
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发表时间：
2019-05-01
影响因子：
6.7
通讯作者：
Chiu, Weihsueh A.
中科院分区：
文献类型：
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作者：
Blanchette, Alexander D.;Grimm, Fabian A.;Chiu, Weihsueh A.
全面QT/校正QT（QTc）（TQT）研究是临床心血管安全性评估的基石。然而，TQT研究是资源密集型的，并且缺乏预测监管关注阈值的临床前模型。我们假设使用来自不同人类受试者样本的诱导多能干细胞（iPSC）衍生的心肌细胞的体外模型可以用作培养皿中的TQT研究。对于10种阳性对照药物和3种阴性对照药物，使用群体贝叶斯模型计算的体外浓度-QTc可准确预测已知的体内浓度-QTc。此外，预测将突破10 ms QTc延长的监管阈值的置信度百分比也与体内证据一致。这种培养皿中的TQT研究由基于群体的iPSC衍生的心肌细胞模型和贝叶斯浓度-QTc建模组成，与现有的体外平台相比具有几个优势，包括更高的通量，更低的成本，以及准确预测低于监管关注阈值的体内浓度范围的能力。
Thorough QT/corrected QT (QTc) (TQT) studies are cornerstones of clinical cardiovascular safety assessment. However, TQT studies are resource intensive, and preclinical models predictive of the threshold of regulatory concern are lacking. We hypothesized that an in vitro model using induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a diverse sample of human subjects can serve as a TQT study in a dish. For 10 positive and 3 negative control drugs, in vitro concentration-QTc, computed using a population Bayesian model, accurately predicted known in vivo concentration-QTc. Moreover, predictions of the percent confidence that the regulatory threshold of 10ms QTc prolongation would be breached were also consistent with in vivo evidence. This TQT study in a dish, consisting of a population-based iPSC-derived cardiomyocyte model and Bayesian concentration-QTc modeling, has several advantages over existing in vitro platforms, including higher throughput, lower cost, and the ability to accurately predict the in vivo concentration range below the threshold of regulatory concern.