title: 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.
abstract: BACKGROUND
  The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte. A set of drugs with known clinical torsade de pointes risk was selected to develop and calibrate the in silico model.
  
  
  RESULTS
  Manual patch-clamp data assessing drug effects on expressed cardiac ion channels were integrated into the O'Hara-Rudy myocyte model modified to include dynamic drug-hERG channel (human Ether-à-go-go-Related Gene) interactions. Together with multichannel pharmacology data, this model predicts that compounds with high torsadogenic risk are more likely to be trapped within the hERG channel and show stronger reverse use dependency of action potential prolongation. Furthermore, drug-induced changes in the amount of electronic charge carried by the late sodium and L-type calcium currents was evaluated as a potential metric for assigning torsadogenic risk.
  
  
  CONCLUSIONS
  Modeling dynamic drug-hERG channel interactions and multi-ion channel pharmacology improves the prediction of torsadogenic risk. With further development, these methods have the potential to improve the regulatory assessment of drug safety models under the CiPA paradigm.
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD. zhihua.li@fda.hhs.gov.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Sara
authors.initials: S
authors.lastname: Dutta
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Sheng
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Phu N
authors.initials: PN
authors.lastname: Tran
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Wendy
authors.initials: W
authors.lastname: Wu
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chang
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Thembi
authors.initials: T
authors.lastname: Mdluli
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: David G
authors.initials: DG
authors.lastname: Strauss
authors.affiliation: From the Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Thomas
authors.initials: T
authors.lastname: Colatsky
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D018570:Risk Assessment; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels
keywords: biomarkers; ion channels; torsade de pointes