title: Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.
abstract: OBJECTIVE
  We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different.
  
  
  METHODS
  A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQTc F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2.
  
  
  RESULTS
  There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml(-1) ), ΔΔQTc F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml(-1) ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml(-1) ). The difference in the two ΔΔQTc F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits.
  
  
  CONCLUSIONS
  Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.
authors.affiliation: EResearch Technology Inc., Philadelphia.
authors.forename: Joel
authors.initials: J
authors.lastname: Morganroth
authors.affiliation: Division of Pharmacometrics, Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Statistical Resources Inc., Chapel Hill, North Carolina, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Thorn
authors.affiliation: Clinical Research Centre, Kitasato University East Hospital, Sagamihara, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: SeaView Research Inc., Miami, Florida.
authors.forename: Stuart
authors.initials: S
authors.lastname: Harris
authors.affiliation: Division of Cardiovascular and Renal Products, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
authors.affiliation: EResearch Technology Inc., Philadelphia.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleiman
authors.affiliation: Gerrards Cross, Buckinghamshire, UK.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Shah
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D044466:Asian People; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000208:ethnology; D008297:Male; D000077266:Moxifloxacin; D011446:Prospective Studies; D044465:White People
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin
keywords: Caucasians; Japanese; QTc interval; ethnicity; moxifloxacin; thorough QT studies