title: Measuring kinetics and potency of hERG block for CiPA.
abstract: BACKGROUND
  The Comprehensive in vitro Proarrhythmic Assay (CiPA) aims to update current cardiac safety testing to better evaluate arrhythmic risk. A central theme of CiPA is the use of in silico approaches to risk prediction incorporating models of drug binding to hERG. To parameterize these models, accurate in vitro measurement of potency and kinetics of block is required. The Ion Channel Working Group was tasked with: i) selecting a protocol that could measure kinetics of block and was easily implementable on automated platforms for future rollout in industry and ii) acquiring a reference dataset using the standardized protocol.
  
  
  METHODS
  Data were acquired using a 'step depolarisation' protocol using manual patch-clamp at ambient temperature.
  
  
  RESULTS
  Potency, kinetics and trapping characteristics of hERG block for the CiPA training panel of twelve drugs were measured. Timecourse of block and trapping characteristics could be reliably measured if the time constant for onset of block was between ~500ms and ~15s. Seven drugs, however had time courses of block faster than this cut-off.
  
  
  CONCLUSIONS
  Here we describe the implementation of the standardized protocol for measurement of kinetics and potency of hERG block for CiPA. The results highlight the challenges in identifying a single protocol to measure hERG block over a range of kinetics. The dataset from this study is being used by the In Silico Working Group to develop models of drug binding for risk prediction and is freely available as a 'gold standard' ambient temperature dataset to evaluate variability across high throughput platforms.
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Monique J
authors.initials: MJ
authors.lastname: Windley
authors.affiliation: AnaBios Corp., 3030 Bunker Hill St., San Diego, CA 92109, USA.
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.affiliation: Coyne Scientific, LLC, 58 Edgewood Ave NE Atlanta, GA 30303, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Fermini
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, University of Bristol, UK.
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: a.hill@victorchang.edu.au.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Hill
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007700:Kinetics; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers
keywords: Acquired long QT; CiPA; Drug screening; Proarrhythmic risk; hERG