title: Impact of electrocardiographic data quality on moxifloxacin response in thorough QT/QTc studies.
abstract: BACKGROUND
  Thorough QT studies are typically conducted for drugs with systemic bioavailability and include a positive control, typically moxifloxacin, with a well-described QTc effect.
  
  
  OBJECTIVE
  This study tested two hypotheses: that (i) re-measuring the QT intervals based on electrocardiogram (ECG) pattern similarity improves the moxifloxacin time profile, and (ii) that study conduct influences the ability to detect a typical moxifloxacin time profile.
  
  
  METHODS
  ECGs from 65 studies with available moxifloxacin plasma concentrations were obtained, including four studies with an unexpected moxifloxacin response. Residual error of a concentration-QT model was evaluated before and after re-measuring the QT interval based on ECG pattern similarity. Intra-replicate heart rate differences were calculated using the original heart rate measurements and the 10-s average heart rates.
  
  
  RESULTS
  Similarity re-measurements reduced the residual error of the model (before vs. after of 8.43 ± 2.00 vs. 7.55 ± 1.86 ms; p < 0.001). For both original and averaged 10-s heart rate, intra-replicate heart rate differences were significantly lower (p < 0.001) in studies with the expected response than in those with an unexpected time profile.
  
  
  CONCLUSIONS
  The pattern similarity measurement methodology reduces the residual error of the model, which influences the time profile of the moxifloxacin response. Accuracy of study conduct, represented by intra-replicate heart rate differences, separated studies with and without the expected moxifloxacin time profile.
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA, lars.johannesen@fda.hhs.gov.
authors.forename: Lars
authors.initials: L
authors.lastname: Johannesen
authors.forename: Christine
authors.initials: C
authors.lastname: Garnett
authors.forename: Marek
authors.initials: M
authors.lastname: Malik
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects* / Q000097:blood; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate; D006801:Humans; D008297:Male; D000077266:Moxifloxacin
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin