Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early-phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects.
EXPERIMENTAL APPROACHWe used a highly automated analysis of ECGs from 46 subjects from a crossover thorough QT/QTc study to detect ΔΔQTcF with moxifloxacin. Using these data, we also simulated (bootstrapped) 1000 datasets of a parallel study with eight subjects receiving moxifloxacin and eight others receiving placebo.
KEY RESULTSThe slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 ms of ΔΔQTcF per μg -1 mL -1 ; at mean C max of 2.95 μg·mL À1 , estimated ΔΔQTcF was 13.4 ms (90% confidence interval 11.3, 15.4 ms). In the 1000 simulated datasets, in 996 datasets, ER modelling showed that the upper bound of the 90% confidence interval for ΔΔQTcF at geometric mean C max exceeded 10 ms. In 895 of these 996 datasets, the slope of the ER relationship was statistically significantly positive. Thus, with a small sample size (eight subjects on active drug and eight on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%.
CONCLUSIONS AND IMPLICATIONSOur study adds to the growing body of data supporting intensive ECG collection and analysis in early-phase studies to estimate QT liability.
AbbreviationsICH, International Conference on Harmonization; LOQ, limit of quantitation; SAD, single ascending dose; TQT, thorough QT/QTc