The Effect of Moxifloxacin on QTc and Implications for the Design of Thorough QT Studies

• Published in: Clinical pharmacology and therapeutics 2008-10, Vol.84 (4), p.475-480
• Main Authors: Bloomfield, DM, Kost, JT, Ghosh, K, Hreniuk, D, Hickey, LA, Guitierrez, MJ, Gottesdiener, K, Wagner, JA
• Format: Article
• Language: English
• Subjects: Adult; Anti-Infective Agents - administration & dosage; Anti-Infective Agents - adverse effects; Aza Compounds - administration & dosage; Aza Compounds - adverse effects; Biological and medical sciences; Cross-Over Studies; Dose-Response Relationship, Drug; Electrocardiography; Female; Fluoroquinolones; Humans; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; Male; Medical sciences; Moxifloxacin; Pharmacology. Drug treatments; Pilot Projects; Quinolines - administration & dosage; Quinolines - adverse effects; Research Design
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2008.33

A number of issues have remained unanswered in the design of “thorough QT” (TQT) studies. In this randomized, placebo‐controlled, two‐period crossover study in 20 healthy subjects, replicate electrocardiograms (ECGs) were recorded on a digital 12‐lead Holter recorder, extracted in a core ECG laboratory, and interpreted manually by a cardiologist. The observed within‐subject variability was slightly greater when time‐matched baselines were employed than when predose baselines were employed, whereas the magnitude of the increase in QTc was similar for both. Moxifloxacin 400 mg was associated with an observed 7.5–12.5 ms increase in the mean placebo‐ and baseline‐corrected QTc interval. A PK‐QTc model estimated a 3.9 ms increase in the QTc interval for every 1,000 ng/ml increase in moxifloxacin concentration. The QTc increases associated with moxifloxacin support the appropriateness of its use as a positive control in TQT studies. This crossover study failed to justify the use of time‐matched baselines rather than the less resource‐intensive predose definition of baseline. Clinical Pharmacology & Therapeutics (2008); 84, 4, 475–480 doi:10.1038/clpt.2008.33