Why the study?
Can exposure-response modelling validated by meal effects on the ECG be used in Phase I studies to demonstrate cardiac safety?
Can exposure-response modelling validated by meal effects on the ECG be used in Phase I studies to demonstrate cardiac safety?
This commentary discusses using meal effects on the ECG to validate concentration-effect analysis in Phase I studies as an alternative to Thorough QT (TQT) studies for demonstrating cardiac safety.
Phase I exposure-response modeling may support QTc safety assessment in select cases; leaves open broader validation before routine regulatory substitution for TQT.
In December 2015, the International Conference of Harmonization (ICH) E14 guideline generated guidance on how exposure-response modelling can be used to characterise the potential for a drug to affect cardiac repolarisation and to modulate the QTc interval. The released Q&A document describes how data from Phase I ascending dose SAD and MAD studies can be used in the right circumstances to be accepted by regulatory bodies as an alternative approach to TQT to demonstrate cardiac safety. While this strategy is now being expanded to all new drugs, this alternative analysis has been extensively used in the past. This commentary discusses the results of a retrospective analysis where a concentration-effect analysis validated by meal effects on the ECG was applied to a Phase I study to investigate the PK, PD and safety of escalating single doses of a highly selective sigma1 receptor antagonist.
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Täubel et al. (2016) studied this question.
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