FDA发文使用iPS人源心肌细胞预测药物心肌毒性

2018-08-20 11:01:42

 

FDA发文使用iPS人源心肌细胞预测药物心肌毒性

ComprehensiveTranslational Assessment of Human- Induced Pluripotent Stem Cell DerivedCardiomyocytes for Evaluating Drug-Induced Arrhythmias

导读:

目前药物监管部门(CFDA,FDA等)要求新药研发中,检测药物对hERG钾离子通道和QT的影响。此法虽然排除了许多会引起torsade de points(TdP,室性扭转性心律失常)的“坏药”,但此法与体内相去甚远,仍有很多药物由于心脏毒性“死于”临床甚至上市后,新的更接近体内的筛选方法需求迫切。

 

本文选取FDA明确心脏效应的25种小分子药物,使用iPS人源心肌细胞,通过MEAVSD方法来预测药物对心脏的影响,以验证新方法的可转化性。

 

一张表吃透这篇文章:

 

 

MEA
 Cor.4U

MEA
 iCell

VSD
 Cor.4U

VSD
 iCell

True Positive

15

9

15

12

False Positive

0

0

0

0

True Negative

6

6

6

6

False Negative

4

10

4

7

Sensitivity

0.79

0.47

0.79

0.63

Specificity

1

1

1

1

 

如果没有吃透,请看下列知识点

1. iPS人源心肌细胞平台特异性极高(1

2. MEAVSD方法均可

3. iPS人源心肌细胞平台敏感度很高,接近临床结果(0.79

4. 敏感度受不同生产厂商来源的影响

5. FDA强力推荐

 

 

关键词:

US Food and Drug Administration (FDA)  美国食品及药物管理局

human induced pluripotent stem cell-derivedCardiomyocytes (iPSC-CMs) iPS人源心肌细胞

rate-corrected action potential duration (APDc) 矫正动作电位持续时间

rate-corrected field potential duration (FPDc) 矫正场电位持续时间

 

Brief summary,

A recent researchfrom the laboratory of US Food and Drug Administration (FDA) claimedhuman induced pluripotent stem cell-derived Cardiomyocytes (iPSC-CMs) asa highly promising in vitro systemthat should be included in pro-arrhythmia assay paradigms. Their resultsconcluded that iPSC-CMs, similar to clinical trial results, demonstrated goodcorrelation between drug-induced rate-corrected action potential duration(APDc) and field potential duration (FPDc) prolongation and clinical trial QTcprolongation. Therefore, iPSC-CM in vitro system would serve as a highthrough-put and accurate drug screening system to check ion channel and insilico modeling prediction of pro-arrhythmic risk.

       The drugscreening strategy regulatory agencies nowadays used is to determine the newdrugs’ abilities to block the human ether-a-go-go (hERG) potassium channel andprolong the QT interval on the electrocardiogram. Although, this strategy couldprevent torsade de points (TdP) inducing drug from reaching the market, thedevelopment of other potential new drugs was also terminated inappropriately.Therefore, there is an immediate need for the development of a new screeningmethod to advance regulatory science in this field.

       This studyperformed a concentration-dependent assay using drugs that caused clinicalcardiac diseases with iPSC-CM in vitro system. The cardiotoxicity ofthose drugs was assessed by 1) their effect on multiple isolated cardiac ionchannels (hERG, L-type Calcium, sodium) using patch clamp assay; and 2) thepro-arrhythmic liability using in silico simulations to reconstruct the humanventricular action potential. Of 20 drugs that exhibited clinical QTcprolongation, 17 caused APDc prolongation and 16 caused FPDc prolongation iniPSC-CMs. Of 14 drugs associated with TdP risk, 10 drugs caused arrhythmias iniPSC-CM and lack of arrhythmic beating in the remaining 4 drugs. In conclusion,this study demonstrated that human iPSC-CMs can be used as a high through-putand accurate drug screening system.

 

Reference

Blinova, K., Stohlman, J.,Vicente, J., et al. (2017).Comprehensive Translational Assessment of Human- Induced Pluripotent Stem CellDerived Cardiomyocytes for Evaluating Drug-InducedArrhythmias, 155(1), 234–247. https://doi.org/10.1093/toxsci/kfw200

欲索取原文,请回复info@helpsci.com.cn即可索取

推荐内容

扫描二维码分享到微信