title: Changes in the QTc interval after administration of flecainide acetate, with and without coadministered paroxetine, in relation to cytochrome P450 2D6 genotype: data from an open-label, two-period, single-sequence crossover study in healthy Korean male subjects.
abstract: BACKGROUND
  Flecainide acetate is a class Ic antiarrythmic agent that is metabolized by the cytochrome P450 (CYP) 2D6 isozyme. A previous open-label, 2-period, single-sequence crossover study in healthy Korean male volunteers found differences in the pharmacokinetics of flecainide between subjects with the CYP2D6 wild-type allele and those with the CYP2D6*10 allele, as well as differences in the pharmacokinetic interaction between flecainide and the CYP2D6 inhibitor paroxetine between genotype groups.
  
  
  OBJECTIVE
  This study evaluated QTc-interval changes after administration of a single oral dose of flecainide, with and without paroxetine, in relation to CYP2D6 genetic polymorphism.
  
  
  METHODS
  This was a follow-on to the previous pharmacokinetic study and used data from the same group of healthy Korean male volunteers. Subjects were grouped by CYP2D6 genotype as follows: CYP2D6*1/*1 or CYP2D6*1/*2 (group 1, extensive metabolizers); CYP2D6*1/*10 (group 2, intermediate metabolizers); and CYP2D6*10/*010 or CYP2D6*10/*36 (group 3, poor metabolizers). Flecainide 200 mg was administered on day 1 (period 1); after a 7-day washout period, subjects received paroxetine 20 mg once daily from day 8 to day 14, and flecainide 200 mg on day 15 (period 2). On days 1 and 15, serial 12-lead ECGs were obtained before flecainide dosing and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. Baseline ECGs were obtained at the same time points on days -1 and 14. Machine-read changes in the QT interval corrected using the Fridericia formula (QTcF) and manually read changes in the QT interval individually corrected using mixed-effects modeling (QTcI) from time-matched baseline were analyzed by genotype and by period (baseline and paroxetine-inhibited state). The QRS duration and JTc interval (QTcF - QRS) were also determined.
  
  
  RESULTS
  Twenty-one healthy volunteers (mean [SD] age, 24.5 [3.0] years; mean height, 173.5 [4.6] cm; mean weight, 69.1 [4.5] kg), 7 in each group, were enrolled in and completed the study. In period 1, all genotype groups had significant increases from time-matched baseline in both the QTcF interval (group 1:17.4 milliseconds [90% CI, 9.9-24.9], P < 0.001; group 2: 11.1 milliseconds [90% CI, 7.9-14.3], P = 0.013; and group 3: 20.5 milliseconds [90% CI, 12.8-28.2], P < 0.001) and the QTcI interval (group 1:15.4 milliseconds [90 % CI, 8.0-22.9], P = 0.001; group 2: 9.1 milliseconds [90% CI, 6.5-11.8], P = 0.030; and group 3:16.4 milliseconds [90% CI, 9.3-23.5], P = 0.001); the extent of increase did not differ significantly between groups. In groups 1 and 2, the least squares mean difference between period 1 and period 2 was statistically significant for the change in QTcF interval (6.5 milliseconds [90 CI, 3.2-9.8], P = 0.002; and 6.7 milliseconds [90% CI, 3.6-9.7], P = 0.001, respectively) and QTcI interval (6.9 milliseconds [90% CI, 4.1-9.8], P < 0.001; and 5.8 milliseconds [90% CI, 3.4-8.3], P < 0.001). In group 3, the least squares mean difference between period 1 and period 2 was statistically significant for the change in QTcI interval (3.9 milliseconds [90% CI, 1.3-6.5], P = 0.015) but not for the change in QT cF interval. The changes in QRS duration did not differ significantly by genotype or period. Consistent with the findings for the QTc interval, the least squares mean difference between period 1 and period 2 was statistically significant for the change in JTc interval in groups 1 and 2 (6.9 milliseconds [90% CI, 3.7-10.2], P = 0.001; and 5.4 milliseconds [90% CI, 2.7-8.2], P = 0.001, respectively) but not in group 3.
  
  
  CONCLUSIONS
  The extent of drug interaction between flecainide and paroxetine, as reflected in the change in QTc interval (used as a pharmacodynamic biomarker), was influenced by the CYP2D6*10 allele in these healthy Korean male volunteers.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: JaeWoo
authors.initials: J
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Jeon
authors.forename: You-Me
authors.initials: YM
authors.lastname: Tae
authors.forename: Sojeong
authors.initials: S
authors.lastname: Yi
authors.forename: SoYoung
authors.initials: S
authors.lastname: Eum
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D004562:Electrocardiography; D005424:Flecainide / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D007723:Korea; D008297:Male; D017374:Paroxetine / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine; D019389:Cytochrome P-450 CYP2D6; D005424:Flecainide