The prespecified CiPA in silico model met all measures for ranking and classifying validation drugs across two datasets, outperforming alternative models for proarrhythmia risk assessment.
Does the CiPA in silico mechanistic model accurately predict proarrhythmia risk of drugs?
The CiPA in silico mechanistic model accurately predicts drug-induced proarrhythmia risk, suggesting it may be fit for regulatory use.
The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are pro-arrhythmic. In response, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) was proposed that integrates multi-ion channel pharmacology data in vitro into a human cardiomyocyte model in silico for proarrhythmia risk assessment. Previously, we reported the model optimization and proarrhythmia metric selection based on CiPA training drugs. In this study, we report the application of the prespecified model and metric to independent CiPA validation drugs. Over two validation datasets, the CiPA model performance meets all pre-specified measures for ranking and classifying validation drugs, and outperforms alternatives, despite some in vitro data differences between the two datasets due to different experimental conditions and quality control procedures. This suggests that the current CiPA model/metric may be fit for regulatory use, and standardization of experimental protocols and quality control criteria could increase the model prediction accuracy even further.
Li et al. (Mon,) conducted a other in Proarrhythmia risk prediction. CiPA in silico model vs. Alternative models was evaluated on Model performance for ranking and classifying validation drugs. The prespecified CiPA in silico model met all measures for ranking and classifying validation drugs across two datasets, outperforming alternative models for proarrhythmia risk assessment.
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