Clinical Therapeutics/Volume 32, Number 4, 2010 April 2010 659 *Current affiliation: Armed Forces Medical Research Institute, Daejeon, Korea. These data have been presented in part as a poster at the 108th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21–24, 2007, Anaheim, California. Accepted for publication March 10, 2010. doi:10.1016/j.clinthera.2010.04.002 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved. ABSTRACT Background: Flecainide acetate is a class Ic antiar- rythmic 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 phar- macokinetics 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 inhibi- tor 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/*10 or CYP2D6*10/*36 (group 3, poor metabolizers). Flecainide 200 mg was adminis- tered 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 (base- line 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 mil- liseconds [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 mil- liseconds [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 be- tween 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, 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 Kyoung Soo Lim, MD, PhD*; In-Jin Jang, MD, PhD; Bo-Hyung Kim, MD, PhD; JaeWoo Kim, MD; Ji-Young Jeon, MS; You-Me Tae, MS; SoJeong Yi, MS; SoYoung Eum, MS; Joo-Youn Cho, PhD; Sang-Goo Shin, MD, PhD; and Kyung-Sang Yu, MD, PhD Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea