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Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells

Authors
  • Kramer, James1
  • Himmel, Herbert M.2
  • Lindqvist, Anders3
  • Stoelzle-Feix, Sonja4
  • Chaudhary, Khuram W.5
  • Li, Dingzhou6
  • Bohme, Georg Andrees7
  • Bridgland-Taylor, Matthew8
  • Hebeisen, Simon9
  • Fan, Jingsong10
  • Renganathan, Muthukrishnan11
  • Imredy, John12
  • Humphries, Edward S. A.13
  • Brinkwirth, Nina4
  • Strassmaier, Tim14
  • Ohtsuki, Atsushi15
  • Danker, Timm16
  • Vanoye, Carlos17
  • Polonchuk, Liudmila18
  • Fermini, Bernard19
  • And 2 more
  • 1 Charles River Laboratories, Cleveland, OH, USA , Cleveland (United States)
  • 2 Safety Pharmacology, Bayer AG, Wuppertal, Germany , Wuppertal (Germany)
  • 3 Sophion Bioscience A/S, Ballerup, Denmark , Ballerup (Denmark)
  • 4 Nanion Technologies GmbH, Munich, Germany , Munich (Germany)
  • 5 Global Safety Pharmacology, GlaxoSmithKline PLC, Collegeville, PA, USA , Collegeville (United States)
  • 6 Drug Safety Research & Development, Pfizer, Groton, CT, USA , Groton (United States)
  • 7 Integrated Drug Discovery, High Content Biology Unit, Sanofi R&D, Vitry-Sur-Seine, France , Vitry-Sur-Seine (France)
  • 8 Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, Astra Zeneca, Cambridge, UK , Cambridge (United Kingdom)
  • 9 B’SYS GmbH, Witterswil, Switzerland , Witterswil (Switzerland)
  • 10 Discovery Toxicology, Bristol-Myers Squibb Company, Princeton, NJ, USA , Princeton (United States)
  • 11 Eurofins Discovery, St. Charles, MO, USA , St. Charles (United States)
  • 12 Merck, West Point, PA, USA , West Point (United States)
  • 13 Metrion Biosciences Ltd., Cambridge, UK , Cambridge (United Kingdom)
  • 14 Nanion Technologies, Livingston, NJ, USA , Livingston (United States)
  • 15 Nanion Technologies Japan K.K., Shinjyuku-ku, Tokyo, Japan , Shinjyuku-ku (Japan)
  • 16 Natural and Medical Science Institute at the University of Tübingen, Reutlingen, Germany , Reutlingen (Germany)
  • 17 Northwestern Feinberg School of Medicine, Chicago, IL, USA , Chicago (United States)
  • 18 Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland , Basel (Switzerland)
  • 19 Novoheart, Vancouver, BC, Canada , Vancouver (Canada)
  • 20 Health and Environmental Sciences Institute, Washington, DC, USA , Washington (United States)
  • 21 AbbVie, Chicago, IL, USA , Chicago (United States)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Mar 27, 2020
Volume
10
Issue
1
Identifiers
DOI: 10.1038/s41598-020-62344-w
Source
Springer Nature
License
Green

Abstract

Automated patch clamp (APC) instruments enable efficient evaluation of electrophysiologic effects of drugs on human cardiac currents in heterologous expression systems. Differences in experimental protocols, instruments, and dissimilar site procedures affect the variability of IC50 values characterizing drug block potency. This impacts the utility of APC platforms for assessing a drug’s cardiac safety margin. We determined variability of APC data from multiple sites that measured blocking potency of 12 blinded drugs (with different levels of proarrhythmic risk) against four human cardiac currents (hERG [IKr], hCav1.2 [L-Type ICa], peak hNav1.5, [Peak INa], late hNav1.5 [Late INa]) with recommended protocols (to minimize variance) using five APC platforms across 17 sites. IC50 variability (25/75 percentiles) differed for drugs and currents (e.g., 10.4-fold for dofetilide block of hERG current and 4-fold for mexiletine block of hNav1.5 current). Within-platform variance predominated for 4 of 12 hERG blocking drugs and 4 of 6 hNav1.5 blocking drugs. hERG and hNav1.5 block. Bland-Altman plots depicted varying agreement across APC platforms. A follow-up survey suggested multiple sources of experimental variability that could be further minimized by stricter adherence to standard protocols. Adoption of best practices would ensure less variable APC datasets and improved safety margins and proarrhythmic risk assessments.

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