Detecting moxifloxacin-induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach

British Journal of Pharmacology
Gopi Krishna PanickerSnehal Kothari

Abstract

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. We 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. The slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 ms of ΔΔQTcF per μg(-1) mL(-1) ; at mean Cmax of 2.95 μg·mL(-1) , 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 Cmax 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 (e...Continue Reading

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Citations

Feb 22, 2018·Antimicrobial Agents and Chemotherapy·Marc WeinerWilliam R Mac Kenzie
Feb 25, 2020·Circulation Research·Pei-Chi YangColleen E Clancy
Sep 12, 2017·International Journal of Clinical Practice·Nicholas D BarwellUNKNOWN Scottish Diabetes Foot Action Group
Apr 20, 2018·Journal of Clinical Pharmacology·J Rick TurnerUNKNOWN Cardiac Safety Research Consortium
Apr 1, 2017·European Heart Journal. Cardiovascular Pharmacotherapy·J Rick TurnerSnehal Kothari
Jul 22, 2021·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Kendra K RadtkeAnthony J Garcia-Prats

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