Nonclinical repolarization assays demonstrated excellent specificity (89-100%) but poor sensitivity for predicting clinical QT prolongation, with 28 of 43 TQT-positive drugs showing discordance.
Do nonclinical repolarization assays accurately predict clinical drug-induced QT prolongation?
Standard nonclinical repolarization assays have poor sensitivity for predicting clinical QT prolongation, highlighting the need to consider indirect and nonelectrophysiological drug effects.
The content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.
Valentin et al. (Fri,) conducted a review in Drug-Induced QTc Prolongation (n=150). Nonclinical repolarization assays (hERG, APD, in vivo QTc) vs. Clinical thorough QT (TQT) studies was evaluated on Concordance between nonclinical repolarization assays and clinical TQT study findings. Nonclinical repolarization assays demonstrated excellent specificity (89-100%) but poor sensitivity for predicting clinical QT prolongation, with 28 of 43 TQT-positive drugs showing discordance.