Cross clinical-experimental-computational qualification of in silico drug trials on human cardiac Purkinje cells for proarrhythmia risk prediction
Authorea Preprints, 1–25.
Background and Purpose Preclinical identification and understanding of drug-induced cardiotoxicity is still a major challenge. The ICH S7B Q&A promote human in silico drug trials for proarrhythmia risk assessment. However, additional evidence is needed to support further regulatory impact and for their integration in the current preclinical assessment pipelines. This study aims to provide a comparative evaluation of drug-induced electrophysiological effects on in silico and in vitro cardiac Purkinje and to assess the accuracy of these models for clinical risk predictions. Experimental Approach The effects of 14 reference compounds were quantified in a population of in silico human cardiac Purkinje models, and compared with results obtained in in vitro rabbit Purkinje preparations. For each drug dose, five electrophysiological biomarkers were quantified at three pacing frequencies, and results compared with clinical proarrhythmia reports. Key Results i) In silico, repolarisation abnormalities in human Purkinje simulations predicted drug-induced arrhythmia for all risky compounds, showing higher predicted accuracy than rabbit experiments; ii) Drug-induced electrophysiological changes observed in human-based simulations showed a high degree of consistency with in vitro rabbit recordings at all pacing frequencies, and depolarisation velocity and action potential duration were the most consistent biomarkers; iii) discrepancies observed for dofetilide, sotalol and terfenadine are mainly caused by species differences between humans and rabbit. Conclusion and Implications In this study, we showed the high degree of consistency and higher accuracy of in silico methods compared to in vitro animal models, demonstrating the high regulatory impact of in silico trials for proarrhythmia prediction.