Proarrhythmic risk assessment using conventional and new in vitro assays

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.