An open-label, single-dose, parallel-group, dose-increasing study comparing the pharmacokinetics and tolerability of pilsicainide hydrochloride in healthy Korean and Japanese male subjects.
BACKGROUND
Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias.


OBJECTIVE
The objective of this study was to compare the pharmacokinetics and tolerability of pilsicainide in healthy Korean and Japanese male volunteers to satisfy regulatory requirements for marketing pilsicainide in the Republic of Korea.


METHODS
This was an open-label, single-dose, parallel-group, dose-increasing study. It was simultaneously conducted in healthy Korean and Japanese volunteers from September 2005 through May 2006; pilsicainide was approved for use in the Republic of Korea in 2007. Subjects for the 100-mg group were enrolled after the performance of tolerability evaluations in the 50-mg dose group. Serial blood and urine samples were collected up to 24 hours after dosing, and drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Tolerability was evaluated by monitoring adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiograms (ECGs).


RESULTS
Sixteen healthy Korean male subjects (mean [SD] age, 24.5 [4.2] years; weight, 71.8 [5.5] kg; height, 176.6 [6.3] cm) and 16 healthy male Japanese subjects (age, 24.7 [4.9] years; weight, 60.2 [4.4] kg; height, 171.9 [6.4] cm) were enrolled in the study. Values for AUC and C(max) of pilsicainide increased proportionally with dose escalation in all subjects. Pilsicainide reached C(max) 0.5 to 1.5 hours after dosing in both the Korean and Japanese subjects. The mean (SD) dose-normalized values for C(max) for the Korean and Japanese subjects were 9.4 (1.9) and 9.2 (1.6) ng/mL/mg, respectively. The mean (SD) dose-normalized values for AUC(0-infinity) were 56.0 (8.0) ng . h/mL/mg in the Korean subjects and 53.8 (8.1) ng . h/mL/mg in the Japanese subjects. None of these findings were statistically significant. A total of 9 AEs occurred in 7 of the 16 Korean subjects; they included dizziness, feeling of being hot, somnolence, and atrioventricular block. All of the AEs were mild in severity and were considered possibly related to pilsicainide. Two of the 16 Japanese subjects had a total of 4 AEs. All of the AEs occurred in the subjects treated with 50 mg. Of the 2 subjects with AEs, 1 subject had a decrease in blood pressure, a sense of discomfort, and PR-interval prolongation on ECG, while the other developed a premature ventricular contraction (PVC). The PR-interval prolongation and PVC were determined to be possibly related to pilsicainide, and these were mild in severity. The other AEs (ie, decreased blood pressure, sense of discomfort) were moderate in severity.


CONCLUSIONS
The results of this study suggest that the pharmacokinetic profile of pilsicainide was not significantly different between these healthy Korean and Japanese male volunteers. A single dose (50 or 100 mg) of pilsicainide was well tolerated in both ethnic groups.
Kim
Bo-Hyung
BH
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Jongno-gu, Seoul, Republic of Korea.
Kim
Jung-Ryul
JR
Lim
Kyoung Soo
KS
Kim
Jae Woo
JW
Kim
Kyu-pyo
KP
Hong
Jang-Hee
JH
Jang
In-Jin
IJ
Shin
Sang-Goo
SG
Yu
Kyung-Sang
KS
Tanaka
Takanori
T
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006801:Humans; D007564:Japan; D007723:Korea; D008012:Lidocaine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D012016:Reference Values; D055815:Young Adult
D000889:Anti-Arrhythmia Agents; D008012:Lidocaine; C042288:pilsicainide