Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

QTc interval prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from the preclinical cardiac repolarization models (hERG, Guinea pig MAP and dog telemetry) on the clinical effects on the QTc interval. A Thorough QT/QTc (TQT) study is generally required for bioavailable pharmaceutical compounds to determine whether a drug shows a QTc effect above a threshold of regulatory interest or not. However, as demonstrated in this AZD3839 Single Ascending Dose (SAD) study, high resolution digital ECG data in combination with adequate efficacy biomarker and pharmacokinetic data and non-linear mixed effects modeling can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the TQT study.