Is a Thorough QTc Study Necessary? The Role of Modeling and Simulation in Evaluating the QTc Prolongation Potential of Drugs

Concentration‐QT (C‐QT) modeling has been conducted for multiple compounds at various stages of development in different therapeutic areas. Data from available single and multiple ascending‐dose (SAD/MAD) studies were pooled to construct population C‐QT models, with post hoc predictions of concentration from a pharmacokinetic model. All SAD and MAD studies employed a customized robust QTc assessment with time‐matched triplicate electrocardiograms and centralized manual QTc reading. Sources of variability were characterized, and the relationship between covariates and model parameters was explored, with a particular emphasis on correction for heart rate and diurnal variation. The results of population prediction of QTc prolongation were compared to available thorough QTc (TQT) study results, and the C‐QT model was evaluated to determine whether it could establish the QTc prolongation relationship without the TQT results. Negative TQT study results confirmed negative simulation results from phase I/II C‐QT models. Simulations were undertaken to characterize the ability of pooled C‐QT modeling to obviate the need for a TQT. C‐QT modeling should be implemented as a standard part of modeling and simulation at different phases of drug development and used in conjunction with other data that influence the need and/or the timing of a TQT study.