title: Contributing factors to the apparent clearance of bepridil in patients with paroxysmal or persistent atrial fibrillation: analysis using population pharmacokinetics.
abstract: BACKGROUND
  Bepridil is used as an antiarrhythmic drug due to its class I, class III, and class IV electrophysiological properties, but it has serious adverse effects such as QT prolongation and torsade de pointes. Bepridil has complex pharmacokinetic (PK) properties with large interindividual differences in plasma concentrations. The aim of this study was to evaluate the contributing factors to changes in the dose-concentration relationship of bepridil and the risk factors for excessive QT prolongation in patients with paroxysmal or persistent atrial fibrillation (AF).
  
  
  METHODS
  A population PK analysis was performed by using NONMEM based on 425 concentration points from 76 patients receiving bepridil. A 1-compartment model approximating an intravenous model was used to examine the interindividual variability of the apparent systematic clearance (CL/F) of bepridil. A population PK-pharmacodynamic analysis was performed using the linear regression.
  
  
  RESULTS
  Age was a contributing factor to the CL/F of bepridil in AF patients. The QTc interval increased as the area under the plasma bepridil concentration time curve (AUC) increased. The AUC in patients without a bundle branch block, the baseline QT interval, and the existence of structural heart disease in patients with a bundle branch block were explanatory variables of excessive QTc prolongation (QTc > 500 ms) during bepridil therapy.
  
  
  CONCLUSIONS
  Using population PK methodology, this study showed that age was a contributing factor to the apparent clearance of bepridil in Japanese patients with AF and that excessive QT prolongation might be related to a larger AUC.
authors.affiliation: Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan. mshiga@hij.twmu.ac.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shiga
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hashiguchi
authors.forename: Miyoko
authors.initials: M
authors.lastname: Naganuma
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Hagiwara
mesh_terms: D000367:Age Factors; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D001281:Atrial Fibrillation / Q000188:drug therapy; D015764:Bepridil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007564:Japan; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012307:Risk Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D015764:Bepridil