title: Improving the assessment of heart toxicity for all new drugs through translational regulatory science.
abstract: Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.
authors: 1] Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA [2] Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA [3] Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors: L
authors: L
authors: Johannesen
authors: 1] Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA [2] Communications Technology Group, Aragón Institute of Engineering Research, IIS Aragón, University of Zaragoza, Zaragoza, Spain.
authors: J
authors: J
authors: Vicente
authors: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors: R A
authors: RA
authors: Gray
authors: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors: L
authors: L
authors: Galeotti
authors: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors: Z
authors: Z
authors: Loring
authors: 1] Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA [2] Certara, Cary, North Carolina, USA.
authors: C E
authors: CE
authors: Garnett
authors: Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors: J
authors: J
authors: Florian
authors: 1] Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA [2] Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors: M
authors: M
authors: Ugander
authors: Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors: N
authors: N
authors: Stockbridge
authors: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors: D G
authors: DG
authors: Strauss
mesh_terms: D002121:Calcium Channel Blockers / Q000009:adverse effects; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D004335:Drug and Narcotic Control; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D026902:Potassium Channel Blockers / Q000009:adverse effects; D026941:Sodium Channel Blockers / Q000009:adverse effects; D016171:Torsades de Pointes / Q000139:chemically induced*; D057170:Translational Research, Biomedical / Q000379:methods*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers