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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.