Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the Ci PA Initiative
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 (Ci PA ) 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 Ci PA training drugs. In this study, we report the application of the prespecified model and metric to independent Ci PA validation drugs. Over two validation datasets, the Ci PA 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 Ci PA 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.
- Authors:
-
- 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
- Department of Computer Science Healthcare Informatics University of Oxford Oxford UK
- Centre for Mathematical Medicine &, Biology School of Mathematical Sciences University of Nottingham Nottingham UK
- Charles River Laboratories Wilmington Massachusetts USA
- CytoBioscience New Orleans Louisiana USA
- Publication Date:
- Research Org.:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); Wellcome Trust; Engineering and Physical Sciences Research Council; U.S. Food and Drug Administration (FDA)
- OSTI Identifier:
- 1493112
- Alternate Identifier(s):
- OSTI ID: 1511073; OSTI ID: 1904991
- Grant/Contract Number:
- SC0014664; 101222/Z/13/Z; EP/G037280/1
- Resource Type:
- Published Article
- Journal Name:
- Clinical Pharmacology and Therapeutics
- Additional Journal Information:
- Journal Name: Clinical Pharmacology and Therapeutics Journal Volume: 105 Journal Issue: 2; Journal ID: ISSN 0009-9236
- Publisher:
- Wiley-Blackwell
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; pharmacology & pharmacy
Citation Formats
Li, Zhihua, Ridder, Bradley J., Han, Xiaomei, Wu, Wendy W., Sheng, Jiansong, Tran, Phu N., Wu, Min, Randolph, Aaron, Johnstone, Ross H., Mirams, Gary R., Kuryshev, Yuri, Kramer, James, Wu, Caiyun, Crumb, Jr., William J., and Strauss, David G. Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the Ci PA Initiative. United States: N. p., 2018.
Web. doi:10.1002/cpt.1184.
Li, Zhihua, Ridder, Bradley J., Han, Xiaomei, Wu, Wendy W., Sheng, Jiansong, Tran, Phu N., Wu, Min, Randolph, Aaron, Johnstone, Ross H., Mirams, Gary R., Kuryshev, Yuri, Kramer, James, Wu, Caiyun, Crumb, Jr., William J., & Strauss, David G. Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the Ci PA Initiative. United States. https://doi.org/10.1002/cpt.1184
Li, Zhihua, Ridder, Bradley J., Han, Xiaomei, Wu, Wendy W., Sheng, Jiansong, Tran, Phu N., Wu, Min, Randolph, Aaron, Johnstone, Ross H., Mirams, Gary R., Kuryshev, Yuri, Kramer, James, Wu, Caiyun, Crumb, Jr., William J., and Strauss, David G. Mon .
"Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the Ci PA Initiative". United States. https://doi.org/10.1002/cpt.1184.
@article{osti_1493112,
title = {Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the Ci PA Initiative},
author = {Li, Zhihua and Ridder, Bradley J. and Han, Xiaomei and Wu, Wendy W. and Sheng, Jiansong and Tran, Phu N. and Wu, Min and Randolph, Aaron and Johnstone, Ross H. and Mirams, Gary R. and Kuryshev, Yuri and Kramer, James and Wu, Caiyun and Crumb, Jr., William J. and Strauss, David G.},
abstractNote = {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 (Ci PA ) 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 Ci PA training drugs. In this study, we report the application of the prespecified model and metric to independent Ci PA validation drugs. Over two validation datasets, the Ci PA 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 Ci PA 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.},
doi = {10.1002/cpt.1184},
journal = {Clinical Pharmacology and Therapeutics},
number = 2,
volume = 105,
place = {United States},
year = {Mon Aug 27 00:00:00 EDT 2018},
month = {Mon Aug 27 00:00:00 EDT 2018}
}
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1002/cpt.1184
https://doi.org/10.1002/cpt.1184
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 87 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel
journal, September 2016
- Crumb, William J.; Vicente, Jose; Johannesen, Lars
- Journal of Pharmacological and Toxicological Methods, Vol. 81
Convergence of models of human ventricular myocyte electrophysiology after global optimization to recapitulate clinical long QT phenotypes
journal, November 2016
- Mann, Stefan A.; Imtiaz, Mohammad; Winbo, Annika
- Journal of Molecular and Cellular Cardiology, Vol. 100
Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator
journal, May 2015
- Okada, Jun-ichi; Yoshinaga, Takashi; Kurokawa, Junko
- Science Advances, Vol. 1, Issue 4
Assessing the Performance of Prediction Models: A Framework for Traditional and Novel Measures
journal, January 2010
- Steyerberg, Ewout W.; Vickers, Andrew J.; Cook, Nancy R.
- Epidemiology, Vol. 21, Issue 1
Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study
journal, November 2017
- Vicente, Jose; Zusterzeel, Robbert; Johannesen, Lars
- Clinical Pharmacology & Therapeutics, Vol. 103, Issue 1
When and How Can Endpoints Be Changed after Initiation of a Randomized Clinical Trial
journal, April 2007
- Evans, Scott
- PLoS Clinical Trials, Vol. 2, Issue 4
MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes
journal, July 2013
- Kramer, James; Obejero-Paz, Carlos A.; Myatt, Glenn
- Scientific Reports, Vol. 3, Issue 1
Uncertainty Quantification Reveals the Importance of Data Variability and Experimental Design Considerations for in Silico Proarrhythmia Risk Assessment
journal, November 2017
- Chang, Kelly C.; Dutta, Sara; Mirams, Gary R.
- Frontiers in Physiology, Vol. 8
Role of concentration-dependent plasma protein binding in disopyramide disposition
journal, February 1979
- Meffin, Peter J.; Robert, Edward W.; Winkle, Roger A.
- Journal of Pharmacokinetics and Biopharmaceutics, Vol. 7, Issue 1
Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment
journal, August 2017
- Dutta, Sara; Chang, Kelly C.; Beattie, Kylie A.
- Frontiers in Physiology, Vol. 8
Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk
journal, February 2011
- Mirams, Gary R.; Cui, Yi; Sher, Anna
- Cardiovascular Research, Vol. 91, Issue 1
Validation of Biomarker-Based Risk Prediction Models
journal, October 2008
- Taylor, J. M. G.; Ankerst, D. P.; Andridge, R. R.
- Clinical Cancer Research, Vol. 14, Issue 19
Verapamil prevents torsade de pointes by reduction of transmural dispersion of repolarization and suppression of early afterdepolarizations in an intact heart model of LQT3
journal, June 2005
- Milberg, P.; Reinsch, N.; Osada, N.
- Basic Research in Cardiology, Vol. 100, Issue 4
Cellular basis of drug-induced torsades de pointes
journal, August 2008
- Roden, D. M.
- British Journal of Pharmacology, Vol. 154, Issue 7
QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone: RISPERIDONE METABOLISM AND QT INTERVAL
journal, December 2011
- Suzuki, Yutaro; Fukui, Naoki; Watanabe, Junzo
- Human Psychopharmacology: Clinical and Experimental, Vol. 27, Issue 1
Domperidone and Ventricular Arrhythmia or Sudden Cardiac Death: A Population-Based Case-Control Study in the Netherlands
journal, January 2010
- van Noord, Charlotte; Dieleman, Jeanne P.; van Herpen, Gerard
- Drug Safety, Vol. 33, Issue 11
Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel–Drug Binding Kinetics and Multichannel Pharmacology
journal, February 2017
- Li, Zhihua; Dutta, Sara; Sheng, Jiansong
- Circulation: Arrhythmia and Electrophysiology, Vol. 10, Issue 2
Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator
journal, January 2017
- McMillan, Beth; Gavaghan, David J.; Mirams, Gary R.
- Toxicology Research, Vol. 6, Issue 6
Investigating dynamic protocol-dependence of hERG potassium channel inhibition at 37°C: Cisapride versus dofetilide
journal, March 2010
- Milnes, James T.; Witchel, Harry J.; Leaney, Joanne L.
- Journal of Pharmacological and Toxicological Methods, Vol. 61, Issue 2
Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation
journal, May 2011
- O'Hara, Thomas; Virág, László; Varró, András
- PLoS Computational Biology, Vol. 7, Issue 5
β-Blockers Protect Against Dispersion of Repolarization During Exercise in Congenital Long-QT Syndrome Type 1
journal, June 2011
- Gemma, Lee W.; Ward, Gregory M.; Dettmer, Mary M.
- Journal of Cardiovascular Electrophysiology, Vol. 22, Issue 10
Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity
journal, September 2017
- Passini, Elisa; Britton, Oliver J.; Lu, Hua Rong
- Frontiers in Physiology, Vol. 8
Complex versus simple models: ion-channel cardiac toxicity prediction
journal, January 2018
- Mistry, Hitesh B.
- PeerJ, Vol. 6
The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative — Update on progress
journal, September 2016
- Colatsky, Thomas; Fermini, Bernard; Gintant, Gary
- Journal of Pharmacological and Toxicological Methods, Vol. 81
RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents
journal, June 2006
- Orth, P.; Hesketh, J.; Mak, C.
- Cardiovascular Research, Vol. 70, Issue 3
Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept
journal, November 2016
- Abbasi, Mitra; Small, Ben G.; Patel, Nikunjkumar
- Toxicology Mechanisms and Methods, Vol. 27, Issue 2
Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium
journal, March 2014
- Sager, Philip T.; Gintant, Gary; Turner, J. Rick
- American Heart Journal, Vol. 167, Issue 3
Global Optimization of Ventricular Myocyte Model to Multi-Variable Objective Improves Predictions of Drug-Induced Torsades de Pointes
journal, December 2017
- Krogh-Madsen, Trine; Jacobson, Anna F.; Ortega, Francis A.
- Frontiers in Physiology, Vol. 8
Pharmacokinetic Factors in the Adverse Cardiovascular Effects of Antipsychotic Drugs
journal, January 2004
- Brown, Candace S.; Farmer, Richard G.; Soberman, Judith E.
- Clinical Pharmacokinetics, Vol. 43, Issue 1
Improved Prediction of Drug-Induced Torsades de Pointes Through Simulations of Dynamics and Machine Learning Algorithms
journal, May 2016
- Lancaster, M. Cummins; Sobie, Ea
- Clinical Pharmacology & Therapeutics, Vol. 100, Issue 4
Torsades de Pointes Ventricular Tachycardia Induced by Clarithromycin and Disopyramide in the Presence of Hypokalemia
journal, April 1999
- Hayashi, Yuji; Ikeda, Uichi; Hashimoto, Tohru
- Pacing and Clinical Electrophysiology, Vol. 22, Issue 4