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: Tsuyoshi Shiga, Masayuki Hashiguchi, Miyoko Naganuma, Atsushi Suzuki, Nobuhisa Hagiwara
• Journal: Therapeutic drug monitoring (Ther Drug Monit) Vol. 35 Issue 3 Pg. 367-73 (Jun 2013) ISSN: 1536-3694 [Electronic] United States
• PMID: 23666576 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Bepridil

Topics

• Age Factors
• Aged
• Anti-Arrhythmia Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Asian People
• Atrial Fibrillation (drug therapy)
• Bepridil (administration & dosage, adverse effects, pharmacokinetics)
• Cohort Studies
• Dose-Response Relationship, Drug
• Drug Monitoring
• Female
• Humans
• Japan
• Linear Models
• Long QT Syndrome (chemically induced, etiology)
• Male
• Middle Aged
• Models, Biological
• Nonlinear Dynamics
• Risk Factors