Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models

Exposure‐response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure‐response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug‐effect exposure‐response models on vital signs and electrocardiogram (ECG) intervals, an individual‐level model‐based meta‐analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross‐validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross‐validated drug‐effect when considering all markers. A linear model was the most commonly selected to characterize drug‐effect on all markers. We propose these models as a starting point assisting with CV safety exposure‐response assessment in nondedicated small studies with healthy subjects.