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KMID : 1177720180120010025
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Journal of Alternatives to Animal Experiments
2018 Volume.12 No. 1 p.25 ~ p.32
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Integrated in vivo cardiac safety evaluation using systemic pharmacology technique
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Oh Kun-Hee
Kim Ki-Suk
Lee Hyang-Ae
Han Seung-Hoon
Yim Dong-Seok
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Abstract
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ICH S7B and E14 guidelines, which were first released in 2005, are focused on hERG blockade and QT prolongation by drugs. However, cumulated evidences on some pitfalls of the guidelines resulted in the initiation of the comprehensive in vitro proarrhythmia assay (CiPA) project. Results of the CiPA are expected to change global regulatory environment on the cardiac safety of drugs. In this study, we reproduced two components of the CiPA to assess the performance of their in silico biomarker using in vitro ion channel assay data. The process to obtain qNET, a biomarker proposed by CiPA, was fully reproduced through in vitro and in silico studies in selected three drugs (verapamil, ranolazine, moxifloxacin). Throughout the reproducing research, we obtained many practical experiences not included in publications by the CiPA. For further understanding of this new regulatory paradigm, clinical ECG in human and another in silico method are to be performed.
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KEYWORD
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CiPA initiative, in vitro ion channel assay, in silico methods, hERG channel, TdP
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