期刊
CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 105, 期 5, 页码 1175-1186出版社
WILEY
DOI: 10.1002/cpt.1259
关键词
-
资金
- National Institutes of Health [P42 ES027704, T32 ES026568]
- United States Environmental Protection Agency [STAR RD83580201]
- Society of Toxicology Colgate-Palmolive Award
- Society of Toxicology Syngenta Fellowship Award
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据