A Conceptual Translational Bench-to-Bedside Cardiac Safety Framework for Predicting Drug-Induced QT Interval Prolongation from Molecular Structure to Clinical Data

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Abstract
QT interval prolongation is associated with an increased risk of torsades de pointes (TdP), a potentially life-threatening ventricular arrhythmia, making assessment of cardiac repolarization a critical component of drug development. This work demonstrates how integrated in silico methodologies can be used to predict and quantitatively characterize QT liability across the drug discovery and development continuum. A proof-of concept translational workflow combining molecular structure analysis, in vitro pharmacology, animal data, and clinical exposure-response modeling was evaluated using the retrospective case examples verapamil and dofetilide. Molecular structure- and pharmacology-based assessments predicted hERG channel interaction and potential QT risk for both compounds. While initial in silico analyses suggested a high QT liability for verapamil and dofetilide, mechanistic electrophysiological modeling differentiated their effects. For verapamil, concurrent calcium channel inhibition offset hERG-mediated effects, resulting in predicted reductions in action potential duration and no clinically relevant QT prolongation. In contrast, dofetilide produced concentration-dependent increases in action potential duration, consistent with its known proarrhythmic potential. Translation of nonclinical findings to humans accurately predicted the absence of clinically meaningful QT effects for verapamil and identified QT prolongation exceeding the regulatory 10 ms threshold for dofetilide at therapeutic concentrations. Drug exposure and pharmacokinetic properties could be anticipated based solely on molecular structure. This conceptual workflow demonstrates how integrated quantitative in silico approaches can support earlier identification, characterization, and communication of QT risk, enabling informed decision-making and improved development efficiency from bench to bedside.
Funding Information
  • Advanced Research Projects Agency for Health (1AY2AX000124)

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