International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment

被引：266

作者：

Blinova, Ksenia ^{[1
]}

Dang, Qianyu ^{[2
]}

Millard, Daniel ^{[3
]}

Smith, Godfrey ^{[4
,5
]}

Pierson, Jennifer ^{[6
]}

Guo, Liang ^{[7
]}

Brock, Mathew ^{[8
]}

Lu, Hua Rong ^{[9
]}

Kraushaar, Udo ^{[10
]}

Zeng, Haoyu ^{[11
]}

Shi, Hong ^{[12
]}

Zhang, Xiaoyu ^{[13
]}

Sawada, Kohei ^{[14
,15
]}

Osada, Tomoharu ^{[16
]}

Kanda, Yasunari ^{[17
]}

Sekino, Yuko ^{[15
,17
]}

Pang, Li ^{[18
]}

Feaster, Tromondae K. ^{[19
]}

Kettenhofen, Ralf ^{[20
]}

Stockbridge, Norman ^{[21
]}

Strauss, David G. ^{[22
]}

Gintant, Gary ^{[23
]}

机构：

[1] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA

[2] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[3] Axion BioSyst, Atlanta, GA 30309 USA

[4] Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland

[5] Clyde Biosci, Newhouse ML1 5UH, Scotland

[6] Hlth & Environm Sci Inst, Washington, DC 20005 USA

[7] Leidos Biomed Res, Frederick Natl Lab Canc Res, Invest Toxicol, Frederick, MD 21702 USA

[8] Genentech Inc, San Francisco, CA 94080 USA

[9] Janssen Pharmaceut JNJ, Discovery Sci R&D, Beerse, Belgium

[10] Univ Tubingen, NMI Nat & Med Sci Inst, Reutlingen, Germany

[11] Merck, Safety & Exploratory Pharmacol Dept, West Point, PA 19486 USA

[12] Bristol Myers Squibb, New York, NY 10154 USA

[13] ACEA Biosci, San Diego, CA 92121 USA

[14] Eisai, Tsukuba, Ibaraki 3002635, Japan

[15] Univ Tokyo, Bunkyo Ku, Tokyo 1130033, Japan

[16] LSI Medience, Chiyoda Ku, Tokyo 1018517, Japan

[17] Natl Inst Hlth Sci, Div Pharmacol, Kawasaki, Kanagawa 2109501, Japan

[18] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA

[19] Cellular Dynam Int, Madison, WI 53711 USA

[20] Ncardia, D-50829 Cologne, Germany

[21] US FDA, Div Cardiovasc & Renal Prod, Off Drug Evaluat 1, Off New Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[22] US FDA, Div Appl & Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[23] AbbVie, N Chicago, IL 60064 USA

来源：

CELL REPORTS | 2018年 / 24卷 / 13期

关键词：

SAFETY PHARMACOLOGY; RISK-ASSESSMENT; DURATION; CURRENTS; HERG;

D O I：

10.1016/j.celrep.2018.08.079

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

To assess the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro proarrhythmia model, we evaluated the concentration dependence and sources of variability of electrophysiologic responses to 28 drugs linked to low, intermediate, and high torsades de pointes (TdP) risk categories using two commercial cell lines and standardized protocols in a blinded multisite study using multielectrode array or voltage-sensing optical approaches. Logistical and ordinal linear regression models were constructed using drug responses as predictors and TdP risk categories as outcomes. Three of seven predictors (drug-induced arrhythmia-like events and prolongation of repolarization at either maximum tested or maximal clinical exposures) categorized drugs with reasonable accuracy (area under the curve values of receiver operator curves similar to 0.8). hiPSC-CM line, test site, and platform had minimal influence on drug categorization. These results demonstrate the utility of hiPSC-CMs to detect drug-induced proarrhythmic effects as part of the evolving Comprehensive In Vitro Proarrhythmia Assay paradigm.

引用

页码：3582 / 3592

页数：11

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