Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative
Zhihua Li, Bradley J Ridder, Xiaomei Han, Wendy W Wu, Jiansong Sheng, Phu N Tran, Min Wu, Aaron Randolph, Ross H Johnstone, Gary R Mirams, Yuri Kuryshev, James Kramer, Caiyun Wu, William J Crumb Jr, David G Strauss, Zhihua Li, Bradley J Ridder, Xiaomei Han, Wendy W Wu, Jiansong Sheng, Phu N Tran, Min Wu, Aaron Randolph, Ross H Johnstone, Gary R Mirams, Yuri Kuryshev, James Kramer, Caiyun Wu, William J Crumb Jr, David G Strauss
Abstract
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.
Conflict of interest statement
Gary Mirams has received research support from consultancy to Oxford University Innovation on projects with Hoffman‐La Roche and GlaxoSmithKline. This report is not an official US Food and Drug Administration guidance or policy statement. No official support or endorsement by the US Food and Drug Administration is intended or should be inferred.
© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.
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