Li2019 - In Silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative

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Model Identifier
MODEL2111260002
Short description
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.
Format
R
Related Publication
  • Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative.
  • Li Z, Ridder BJ, Han X, Wu WW, Sheng J, Tran PN, Wu M, Randolph A, Johnstone RH, Mirams GR, Kuryshev Y, Kramer J, Wu C, Crumb WJ Jr, Strauss DG
  • Clinical pharmacology and therapeutics , 2/ 2019 , Volume 105 , Issue 2 , pages: 466-475 , PubMed ID: 30151907
  • Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
  • 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.
Contributors
Krishna Kumar Tiwari

Metadata information


Curation status
Non-curated


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Model files

CiPA-master.zip All files downloaded from https://github.com/FDA/CiPA 28.87 MB Preview | Download

  • Model originally submitted by : Krishna Kumar Tiwari
  • Submitted: Nov 26, 2021 9:24:36 AM
  • Last Modified: Nov 26, 2021 9:24:36 AM
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  • Version: 1 public model Download this version
    • Submitted on: Nov 26, 2021 9:24:36 AM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Import of Li2019 - In Silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative