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Comprehensive in vitro Proarrhythmia Assay (CiPA) 기반 Torsade Metric Score (TMS)를 이용한 TdP 발생 약물의 위험군 분류 성능 평가

Evaluation of Risk Classification Performance of TdP Incidence Drugs Using Torsade Metric Score (TMS) based on Comprehensive in vitro Proarrhythmia Assay (CiPA)

정다운|박성준|강현수|김기석|김배환|임기무|윤승현|남유리|유예담
한국동물실험대체법학회 (Korean Society for Alternatives to Animal Experiments)|2021.12|한국동물실험대체법학회지 (Journal of Alternatives to Animal Experiments)|제15권 제1호|pp. 23-43

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키워드

CardiotoxicityCiPA initiativeTdPqNETTorsade Metric Score

초록

For the assessment of cardiotoxicity and Torsade de Pointes (TdP), a fatal arrhythmic symptom, ICH S7B and E14 guidelines were presented. However, focusing on hERG block, which are essential determinants of arrhythmic risk, may unexpectedly limit drug development by increasing the risk of drugs that are actually non-toxic. To compensate for these problems, the Comprehensive in vitro Proarrhythmic Assay (CiPA) project was proposed. In this study, based on the CiPA project and previous studies, the nine drugs were tested using in vitro multiple ion channel screening on both temperature conditions (room temperature and 37℃). Using the in vitro results, in silico computer simulation was performed based on the O'Hara-Rudy human ventricular myocyte model, and same as the CiPA project obtained a new biomarker, qNet. The in silico computer simulation was performed using 2000 samples of IC50 values extracted by R code. The nine test drugs were associated with cardiotoxicity and TdP, and were selected by the CiPA project and previous studies. Furthermore, as in previous studies, Torsade Metic Score (TMS), the mean qNet value averaged across 1–4 × Cmax, and the threshold was calculated. As a result, the nine tested drugs using the TMS were well plotted by the risk categories and the threshold was able to well classify the risk categories by grade on both temperature conditions. In particular, the threshold 2 value confirmed to significant difference depending on the temperature conditions. The range of threshold narrowed at 37℃, which can be considered as having the ability to distinguish more finely. It shows the correlation with the CiPA project’s validity that a study should be tested at a physiological temperature of 3 7℃. In this study, using the method proposed by the CiPA project, it was possible to predict the risk groups of drugs more accurately, which could be presented as a new paradigm in the cardiotoxicity assessment.

Abstract

For the assessment of cardiotoxicity and Torsade de Pointes (TdP), a fatal arrhythmic symptom, ICH S7B and E14 guidelines were presented. However, focusing on hERG block, which are essential determinants of arrhythmic risk, may unexpectedly limit drug development by increasing the risk of drugs that are actually non-toxic. To compensate for these problems, the Comprehensive in vitro Proarrhythmic Assay (CiPA) project was proposed. In this study, based on the CiPA project and previous studies, the nine drugs were tested using in vitro multiple ion channel screening on both temperature conditions (room temperature and 37℃). Using the in vitro results, in silico computer simulation was performed based on the O'Hara-Rudy human ventricular myocyte model, and same as the CiPA project obtained a new biomarker, qNet. The in silico computer simulation was performed using 2000 samples of IC50 values extracted by R code. The nine test drugs were associated with cardiotoxicity and TdP, and were selected by the CiPA project and previous studies. Furthermore, as in previous studies, Torsade Metic Score (TMS), the mean qNet value averaged across 1–4 × Cmax, and the threshold was calculated. As a result, the nine tested drugs using the TMS were well plotted by the risk categories and the threshold was able to well classify the risk categories by grade on both temperature conditions. In particular, the threshold 2 value confirmed to significant difference depending on the temperature conditions. The range of threshold narrowed at 37℃, which can be considered as having the ability to distinguish more finely. It shows the correlation with the CiPA project’s validity that a study should be tested at a physiological temperature of 3 7℃. In this study, using the method proposed by the CiPA project, it was possible to predict the risk groups of drugs more accurately, which could be presented as a new paradigm in the cardiotoxicity assessment.

참고문헌 (24)

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