title: Characterization of the human QT interval: novel distribution-based assessment of the repolarization effects of moxifloxacin.
abstract: The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer. Distribution-based analysis was applied to the placebo and moxifloxacin (400 mg) arms to characterize the nature of the QT interval and to assess the efficacy of distribution-based analysis for QTc determination. Novel statistics using continuous means and bootstrapped 95% confidence intervals were developed to facilitate QT analysis. Machine-read QT values were compared with core laboratory semiautomated values for verification. RR intervals demonstrated repetitive protocol-dependent variations (50-250 milliseconds); QT intervals were normally distributed, spanning 60 to 100 milliseconds for each RR interval. Distribution-based analysis detected a moxifloxacin response identical to semiautomated analysis, but with reduced variability and improved statistical power, where n = 12 satisfied the ICH E14 criteria for a positive control. Distribution-based analysis has the potential to provide a universal method for clinical QT heart rate correction, enabling accurate detection of QT changes when limited numbers of volunteers are exposed to drug.
authors.affiliation: Department of Toxicology, Charles River Laboratories, Reno, NV 89511, USA. Henry.Holzgrefe@crl.com
authors.forename: Henry H
authors.initials: HH
authors.lastname: Holzgrefe
authors.forename: Georg
authors.initials: G
authors.lastname: Ferber
authors.forename: Royce
authors.initials: R
authors.lastname: Morrison
authors.forename: Olivier
authors.initials: O
authors.lastname: Meyer
authors.forename: Andrea
authors.initials: A
authors.lastname: Greiter-Wilke
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
mesh_terms: D000328:Adult; D001372:Aza Compounds / Q000627:therapeutic use*; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin