title: Detecting moxifloxacin-induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 (eight subjects on active drug and eight on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%.
  
  
  CONCLUSIONS
  Our study adds to the growing body of data supporting intensive ECG collection and analysis in early-phase studies to estimate QT liability.
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Gopi Krishna
authors.initials: GK
authors.lastname: Panicker
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Dilip R
authors.initials: DR
authors.lastname: Karnad
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Pramod
authors.initials: P
authors.lastname: Kadam
authors.affiliation: AMPS LLC, New York, NY, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Badilini
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Damle
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Snehal
authors.initials: S
authors.lastname: Kothari
mesh_terms: D001331:Automation; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis*; D008297:Male; D000077266:Moxifloxacin
chemical_list: D024841:Fluoroquinolones; D000077266:Moxifloxacin