title: Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.
abstract: OBJECTIVE
  The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.
  
  
  RESULTS
  We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.
  
  
  CONCLUSIONS
  The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK. gary.mirams@dpag.ox.ac.uk
authors.forename: Gary R
authors.initials: GR
authors.lastname: Mirams
authors.forename: Yi
authors.initials: Y
authors.lastname: Cui
authors.forename: Anna
authors.initials: A
authors.lastname: Sher
authors.forename: Martin
authors.initials: M
authors.lastname: Fink
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cooper
authors.forename: Bronagh M
authors.initials: BM
authors.lastname: Heath
authors.forename: Nick C
authors.initials: NC
authors.lastname: McMahon
authors.forename: David J
authors.initials: DJ
authors.lastname: Gavaghan
authors.forename: Denis
authors.initials: D
authors.lastname: Noble
mesh_terms: D000200:Action Potentials; D000818:Animals; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008955:Models, Cardiovascular; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D011817:Rabbits; D018570:Risk Assessment; D012307:Risk Factors; D026941:Sodium Channel Blockers / Q000009:adverse effects*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; C000606913:KCNH2 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels