The Challenges of Predicting Drug-Induced QTc Prolongation in Humans

Area of Science:

• Pharmacology
• Cardiovascular Toxicology
• Drug Development

Background:

• Cardiac safety is critical in drug development.
• The thorough QT (TQT) study is the gold standard for assessing clinical QT prolongation.
• Nonclinical assays are used to predict potential QT prolongation.

Purpose of the Study:

• To evaluate the concordance between nonclinical repolarization assays and clinical TQT studies.
• To investigate mechanisms underlying discrepancies between nonclinical and clinical findings.
• To identify best practices for improving cardiac safety assessment in drug development.

Main Methods:

• Conducted a detailed literature review and retrospective analysis of 150 drug candidates.
• Utilized a joint Health and Environmental Sciences Institute (HESI)/Food and Drug Administration (FDA) database.
• Compared three standard nonclinical assays (IKr block, action potential duration, in vivo corrected QT) with clinical TQT study findings.

Main Results:

• Nonclinical assays demonstrated good specificity but poor sensitivity in predicting clinical QT prolongation.
• Identified 28 discordant TQT-positive drugs.
• Examined direct and indirect mechanisms, including effects on other ion channels and heart rate, contributing to discrepancies.

Conclusions:

• Current nonclinical assays have limitations in predicting clinical QT prolongation.
• Discrepancies arise from inadequate nonclinical data, off-target effects, and indirect drug actions.
• Refined methodologies and best practices are needed for accurate cardiac safety evaluation.