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Characterization of the Human QT Interval: Novel Distribution‐Based Assessment of the Repolarization Effects of Moxifloxacin
Author(s) -
Holzgrefe Henry H.,
Ferber Georg,
Morrison Royce,
Meyer Olivier,
GreiterWilke Andrea,
Singer Thomas
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011409234
Subject(s) - moxifloxacin , qt interval , repolarization , medicine , cardiology , interval (graph theory) , distribution (mathematics) , mathematics , chemistry , electrophysiology , antibiotics , mathematical analysis , combinatorics , biochemistry
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.