Cardiovascular safety assessment in early-phase clinical studies: A meta-analytical comparison of exposure-response models

Abstract

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.