title: Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects.
abstract: The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences.
  
  
  
  This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic-pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method.
  
  
  
  A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration-effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emaxmodel (E[C]=[Emax⋅C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic-pharmacodynamic link model.
  
  
  
  The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Hyang-Ki
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Jin Ah
authors.initials: JA
authors.lastname: Jung
authors.affiliation: Kitasato University Hospital, Clinical Trial Center, Kanagawa, Japan; Kitasato University School of Medicine, Department of Pharmacology, Kanagawa, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Kitasato University School of Medicine, Department of Pharmacology, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Amano
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Ghim
authors.affiliation: Department of Clinical Pharmacology, Busan National University Hospital, Busan, Republic of Korea.
authors.forename: Dong-Hwan
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Kitasato University School of Medicine, Department of Urology, Kanagawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Tabata
authors.affiliation: Kitasato University Hospital, Clinical Trial Center, Kanagawa, Japan; Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan.
authors.forename: Il-Dae
authors.initials: ID
authors.lastname: Song
authors.affiliation: Kitasato University Hospital, Clinical Trial Center, Kanagawa, Japan; Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Kitasato University Hospital, Clinical Trial Center, Kanagawa, Japan; Kitasato University School of Medicine, Kitasato Clinical Research Center, Kanagawa, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Cardiac Safety Consultants LTD, London, England.
authors.forename: Boaz
authors.initials: B
authors.lastname: Mendzelevski
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea. Electronic address: phshinjg@gmail.com.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D044466:Asian People; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin
keywords: Japanese; Korean; QT interval prolongation; ethnic difference; moxifloxacin