Concentration-QTc analysis integrated into a Phase 1 Japanese bridging study

[Speaker] Jorg Taubel:1,2
[Co-author] Ulrike Lorch:1, Simon Coates:1, Dilshat Djumanov:1, Georg Ferber:3
1:Richmond Pharmacology Ltd, UK, 2:St Georges University of London, UK, 3:Statistik Georg Ferber, Switzerland

Background: Evaluation of drug effects on the QTc interval, in accordance with ICH (E14), can now be integrated into early phase clinical trials. The concentration-QTc assessment in early stages of clinical development commonly evaluates higher investigational drug concentrations than later stages because the aim is to define dose-limiting toxicity. These higher exposures provide the supratherapeutic concentrations to fulfil regulatory requirements. The role of acetylcholine receptors in cardiac function make QTc evaluation salient to the identification of off-target actions.
Method: A Phase 1 trial included 54 male Japanese and Caucasian subjects in equal proportions. Serial ECG recordings and PK measurements were paired to allow concentration-QTc analysis following administration of a cholinomimetic agent. The exposure-QTc relationship was analyzed using a linear mixed effects model with fixed effects in the form:
deltaQTcF ~ C*race + T + BL + race.
The methodology of ECG acquisition followed principles established for thorough QT (TQT) studies.
Results: The preliminary analysis (Figure 1) showed an absence of any QTc prolonging effect at the concentrations tested. There were non-significant differences between Caucasian and Japanese subjects in line with similar findings reported in literature. The sensitivity to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF after a standardized meal.
Conclusions: The low variability of the QTc results and the assay validation via food effect on QTc-reduction confirm that concentration/QTc analysis can be successfully integrated into small Phase 1 trials. This study showed that the cholinomimetic agent tested showed no repolarization prolongation of regulatory concern.

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