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Proarrhythmic risk assessment using conventional and new in vitro assays

Sonia Goineau1, Vincent Castagné1

  • 1Porsolt, Z.A. de Glatigné, 53940 Le Genest-Saint-Isle, France.

Regulatory Toxicology and Pharmacology : RTP
|May 17, 2017
PubMed

Insights

This study highlights human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a predictive in vitro model for assessing drug-induced cardiac safety. hiPSC-CMs accurately identified QT prolongation risks, improving drug discovery safety evaluations.

Area of Science:

  • Cardiovascular Pharmacology
  • Drug Safety Evaluation
  • Stem Cell Biology

Background:

  • Drug-induced QT prolongation poses significant risks during drug development.
  • Established preclinical assays like hERG channel and Purkinje fiber action potential assays are used for safety assessments.

Purpose of the Study:

  • To evaluate the electrophysiological responses of four substances using traditional assays and a novel human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)-field potential assay.
  • To assess the predictive validity of hiPSC-CMs for identifying drug-induced cardiac safety issues.

Main Methods:

  • Utilized established preclinical assays (hERG channel, Purkinje fiber action potential) and a new hiPSC-CMs-field potential assay.
  • Assessed acute and overnight exposure effects of moxifloxacin, dofetilide, pentamidine, and arsenic on electrophysiological parameters.

Main Results:

  • Moxifloxacin and dofetilide concentration-dependently decreased IKr amplitude and lengthened action and field potential durations.
  • Dofetilide induced arrhythmia in hiPSC-CMs at 30 nM.
  • Pentamidine and arsenic showed effects on IKr and field potential duration after overnight incubation, but not acute exposure.

Conclusions:

  • hiPSC-CMs serve as a functional cellular electrophysiology model that enhances the predictive validity of in vitro safety studies.
  • This model can improve early-stage drug safety assessments, potentially reducing late-stage failures.
Keywords:
Action potentialArrhythmiaCardiac safety pharmacologyField potentialHuman-induced pluripotent stem cell-derived cardiomyocytesMultielectrode arraysPurkinje fiberhERG channel

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