title: Statistical characteristics of moxifloxacin-induced QTc effect.
abstract: Moxifloxacin has been the most commonly used positive control in "thorough" QTc (TQT) studies. In a TQT study, the assay sensitivity is often considered to be established if the baseline corrected mean difference in QTc between moxifloxacin and placebo is greater than 5 ms in common practice at one or more prespecified time points and the observed moxifloxacin induced QTc effect over time follows the proper pharmacokinetics profile. To better understand the statistical characteristics of moxifloxacin-induced QTc prolongation and to provide guidance for future studies, 20 TQT studies that involved moxifloxacin have been evaluated. We study the QTc profile of the baseline adjusted mean difference in QTc between moxifloxacin and placebo over time. Zhang (2008) proposed that the moxifloxacin induced QTc effect can be evaluated between 1 and 4 h after a single dose (400 mg) administration near the time (T(max)) of peak concentration instead of all time points (typically 9-12 time points) at which QT was measured for the study drug evaluation. After evaluating 20 TQT studies, we confirm that the maximum moxifloxacin effect occurs in the time window between 1 and 4 h post dose. We also investigate the variability of the data as well as correlations between time points and between regimens. These findings and results can be used as a reference for future studies.
authors.affiliation: Division of Biometrics VI, Office of Biostatistics/Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Lihan K
authors.initials: LK
authors.lastname: Yan
authors.forename: Joanne
authors.initials: J
authors.lastname: Zhang
authors.forename: Moh Jee
authors.initials: MJ
authors.lastname: Ng
authors.forename: Qianyu
authors.initials: Q
authors.lastname: Dang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D001372:Aza Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018849:Controlled Clinical Trials as Topic / Q000706:statistics & numerical data*; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004562:Electrocardiography / Q000706:statistics & numerical data; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D000077266:Moxifloxacin; D015990:Placebo Effect; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D012016:Reference Values; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin