title: Is a thorough QTc study necessary? The role of modeling and simulation in evaluating the QTc prolongation potential of drugs.
abstract: 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.
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ 08837, USA. Srohatagi@dsus.com
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Carrothers
authors.forename: Jon
authors.initials: J
authors.lastname: Kuwabara-Wagg
authors.forename: Tatiana
authors.initials: T
authors.lastname: Khariton
mesh_terms: D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008955:Models, Cardiovascular; D010599:Pharmacokinetics; D016032:Randomized Controlled Trials as Topic