title: Establishing assay sensitivity in QT studies: experience with the use of moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a thorough QT study.
abstract: OBJECTIVE
  To compare the effect of moxifloxacin as a positive control in a single ascending dose (SAD) study with that in a thorough QT (TQT) study.
  
  
  METHODS
  Moxifloxacin was used as a positive control in a SAD study and a TQT study during the evaluation of the QT liability of a new drug. The SAD study had enrolled 24 males and the TQT study 25 males. Both studies intensively monitored electrocardiograms (ECGs) and pharmacokinetic sampling. Effect of moxifloxacin on QTc interval was analysed in each study by intersection union test (IUT) and by exposure-response (ER) analysis and the results compared. Cost-effectiveness of this approach was computed.
  
  
  RESULTS
  Analysis by IUT revealed that the maximum mean (90 % confidence interval (CI)) placebo-corrected change from baseline (ΔΔQTcF) in the SAD study and the TQT study were remarkably similar (10.7 (6.5; 14.9) ms vs. 9.09 (6.20; 11.98) ms, respectively). In both studies, assay sensitivity was established by the 90 % lower bound exceeding 5 ms. ER analysis revealed the slopes in both studies to be significantly different from zero and comparable. Bootstrap-predicted effects of moxifloxacin at geometric mean concentrations of ~3000 ng/mL were 8.19 (90 % CI 5.86; 10.7) ms in the SAD study and 7.33 (90 % CI 5.69; 9.70) ms in the TQT study.
  
  
  CONCLUSIONS
  Moxifloxacin can be integrated effectively in a SAD study to establish assay sensitivity, and a TQT study may be replaced by a SAD study which has the required assay sensitivity. Further experience is warranted to verify this conclusion.
authors.affiliation: , 8 Birchdale, Gerrards Cross, SL9 7JA, UK. clinical.safety@hotmail.co.uk.
authors.forename: Rashmi R
authors.initials: RR
authors.lastname: Shah
authors.affiliation: Hôpital Bichat, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maison-Blanche
authors.affiliation: Bioprojet Pharma, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Duvauchelle
authors.affiliation: Bioprojet Biotech, Saint Gregoire, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Robert
authors.affiliation: Bioprojet Biotech, Saint Gregoire, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Denis
mesh_terms: D000293:Adolescent; D000328:Adult; D003362:Cost-Benefit Analysis; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000379:methods*; D005240:Feasibility Studies; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D024841:Fluoroquinolones; D000077266:Moxifloxacin
keywords: Assay sensitivity; Exposure-response analysis; ICH E14; Intersection union test; Single ascending dose study; Thorough QT study