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Area of Science:

  • Cardiovascular Pharmacology
  • Drug Safety Assessment
  • In Vitro Toxicology

Background:

  • The Comprehensive in vitro proarrhythmia assay (CiPA) initiative provides a framework for assessing drug-induced arrhythmia risk.
  • Sildenafil (a PDE5 inhibitor) misuse has been reported, necessitating evaluation of its proarrhythmic potential at high concentrations.

Purpose of the Study:

  • To evaluate the proarrhythmic risk of sildenafil under simulated misuse conditions (up to 100× Cmax) using the CiPA framework.
  • To compare in silico predictions with functional assay results for sildenafil's cardiac safety.

Main Methods:

  • Conducted patch clamp assays on HEK293 and CHO cells expressing key cardiac ion channels (Nav1.5, Cav1.2, hERG).
  • Performed in silico modeling using the CiPAORdv1.0 model.
  • Utilized multi-electrode array (MEA) recordings in hiPSC-CMs and in vivo ECG in rats.

Main Results:

  • Sildenafil inhibited hERG currents by 40.5% at 100× Cmax.
  • In silico modeling predicted low Torsades de Pointes (TdP) risk, while MEA recordings indicated a 64% TdP risk and significant FPDc prolongation.
  • In vivo ECG showed significant QT prolongation at 50× Cmax.

Conclusions:

  • Functional assays suggest high-dose sildenafil poses a clinically relevant risk of QT prolongation and arrhythmia, despite low in silico TdP predictions.
  • This study highlights discrepancies between in silico and functional assessments for sildenafil's proarrhythmic potential.
  • Findings underscore the importance of integrated approaches for drug safety evaluation, especially in cases of drug misuse.