CSAHi study: Evaluation of multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia ‿Effects of 7 reference compounds at 10 facilities

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• 作者：Takashi Kitaguchi^a ; ^b ; ^c ; ¹ ; ^{takashi.kitaguchi@mochida.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Yuta Moriyama^b ; ^c ; ¹ ; Tomohiko Taniguchi^b ; ^d ; ¹ ; Atsuko Ojima^b ; ^d ; ¹ ; Hiroyuki Ando^b ; ^e ; ¹ ; Takaaki Uda^b ; ^e ; ¹ ; Koji Otabe^b ; ^f ; ¹ ; Masao Oguchi^b ; ^f ; ¹ ; Shigekazu Shimizu^b ; ^g ; ¹ ; Hiroyuki Saito^b ; ^g ; ¹ ; Maya Morita^b ; ^h ; ¹ ; Atsushi Toratani^b ; ⁱ ; ¹ ; Mahoko Asayama^b ; ⁱ ; ¹ ; Wataru Yamamoto^b ; ^j ; ¹ ; Emi Matsumoto^b ; ^j ; ¹ ; Daisuke Saji^b ; ^k ; ¹ ; Hiroki Ohnaka^b ; ^k ; ¹ ; Kohji Tanaka^b ; ^l ; ¹ ; Ikumi Washio^b ; ^l ; ¹ ; Norimasa Miyamoto^a ; ^b ; ^d ; ¹
• 刊名：Journal of Pharmacological and Toxicological Methods
• 出版年：2016
• 出版时间：March-April 2016
• 年：2016
• 卷：78
• 期：Complete
• 页码：93-102
• 全文大小：1630 K

文摘

Drug-induced QT prolongation is a major safety issue during drug development because it may lead to lethal ventricular arrhythmias. In this study, we evaluated the utility of multi-electrode arrays (MEA) with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to predict drug-induced QT prolongation and arrhythmia.

Methods

Ten facilities evaluated the effects of 7 reference drugs (E-4031, moxifloxacin, flecainide, terfenadine, chromanol 293B, verapamil, and aspirin) using a MED64 MEA system with commercially available hiPS-CMs. Field potential duration (FPD), beat rate, FPD corrected by Fridericia's formula (FPDc), concentration inducing FPDc prolongation by 10% (FPDc₁₀), and incidence of arrhythmia-like waveform were evaluated.

Results

The inter-facility variability of absolute values before drug application was similar to the intra-facility variability for FPD, beat rate, and FPDc. The inter-facility variability of FPDc₁₀ for 5 reference drugs ranged from 1.8- to 5.8-fold. At all 10 facilities, E-4031, moxifloxacin, and flecainide prolonged FPDc and induced arrhythmia-like waveforms at concentrations 1.8- to 6.1-fold higher than their FPDc₁₀. Terfenadine prolonged FPDc and induced beating arrest at 8.0 times the FPDc₁₀. The average FPDc₁₀ values for E-4031, moxifloxacin, and terfenadine were comparable to reported plasma concentrations that caused QT prolongation or Torsade de Pointes in humans. Chromanol 293B, a I_Ks blocker, also prolonged FPDc but did not induce arrhythmia-like waveforms, even at 7.4 times the FPDc₁₀. In contrast, verapamil shortened FPDc and aspirin did not affect FPDc or FP waveforms.

Discussion

MEA with hiPS-CMs can be a generalizable method for accurately predicting both QT prolongation and arrhythmogenic liability in humans.