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.
Biotherapeutics Clinical Pharmacology, Pfizer Global Research and Development, Cambridge, Massachusetts, USA.
D J
DJ
Conrado
Biotherapeutics Clinical Pharmacology, Pfizer Global Research and Development, Cambridge, Massachusetts, USA.
D
D
Chen
Biotherapeutics Clinical Pharmacology, Pfizer Global Research and Development, Cambridge, Massachusetts, USA.
W S
WS
Denney
D015415:Biomarkers / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000503:physiopathology; D002986:Clinical Trials as Topic / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis*; D004562:Electrocardiography; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced; D008962:Models, Theoretical
D015415:Biomarkers