Risks encountered when not adjusting for diurnal variation and food effect in QTcF analysis based on Phase I data
About the publication
Phase I studies are increasingly used to assess drug QT liability—the risk that a compound may prolong the QT interval on an electrocardiogram (ECG). This measurement serves as a critical indicator of cardiac risk and represents a fundamental safety concern in drug development.
However, these early-phase trials often lack the strict controls for meal intake and sampling times found in dedicated “thorough QT” (TQT) studies. Without such standardization, significant variability can be introduced, potentially masking or exaggerating the perceived proarrhythmic risk.
This latest publication, authored by Maddlie Bardol, Andrea Henrich, Céline Sarr, Enrica Mezzalana, and Jürgen Langenhorst in the Journal of Pharmacokinetics and Pharmacodynamics, uses simulation analysis to examine how the uncontrolled factors affect the reliability of concentration-QTc modeling.
Key conclusions include
- Unadjusted models in suboptimal study designs resulted in false-negative rates as high as 50%, potentially masking genuine QT liability.
- Adjusting the models for food status and clock time successfully corrected these imbalances.
- Rigorous documentation of dosing, sampling, and meal times is essential for reliable safety analysis.
By adjusting for known influential factors, researchers can ensure the reliability of concentration-QTc analyses and avoid false-negative conclusions.
This approach strengthens the value of early clinical data to potentially waive dedicated TQT studies, streamlining the drug development process.
