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CSAHi study: Evaluation of multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict
Takashi Kitaguchi1, Yuta Moriyama2, Tomohiko Taniguchi3
1Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), 2-3-11 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Discovery Research, Mochida Pharmaceutical Co., Ltd., 722, Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
Introduction:
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 IKs 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.
Insights
Multi-electrode arrays (MEA) with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) accurately predict drug-induced QT prolongation and arrhythmia risk. This method offers a generalizable approach for drug safety assessment in preclinical development.
Area of Science:
- Cardiovascular Pharmacology
- Stem Cell Biology
- Drug Safety Evaluation
Background:
- Drug-induced QT prolongation is a critical safety concern in drug development, potentially causing fatal arrhythmias.
- Predicting this risk is essential for ensuring patient safety and successful drug progression.
Purpose of the Study:
- To evaluate the utility of multi-electrode arrays (MEA) using human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) for predicting drug-induced QT prolongation and arrhythmia.
- To assess the generalizability and accuracy of this in vitro model across multiple testing facilities.
Main Methods:
- Ten independent facilities utilized MED64 MEA systems with hiPS-CMs to test seven reference drugs.
- Evaluated parameters included field potential duration (FPD), beat rate, corrected FPD (FPDc), concentration for 10% FPDc prolongation (FPDc10), and arrhythmia incidence.
Main Results:
- Inter-facility variability for baseline measurements was comparable to intra-facility variability.
- MEA with hiPS-CMs successfully identified known QT prolonging and arrhythmia-inducing drugs (e.g., E-4031, moxifloxacin, flecainide, terfenadine).
- Results for key drugs correlated with human clinical data on QT prolongation and Torsade de Pointes.
Conclusions:
- MEA combined with hiPS-CMs provides a generalizable and accurate method for predicting drug-induced QT prolongation.
- This approach effectively assesses arrhythmogenic liability, supporting its use in preclinical drug safety screening.
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