Cross clinical-experimental-computational qualification of in silico
drug trials on human cardiac Purkinje cells for proarrhythmia risk
prediction
Abstract
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.