Possible interethnic differences in quinidine‐induced QT prolongation between healthy Caucasian and Korean subjects

Abstract

AimsThe aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in healthy Caucasian and Korean subjects to investigate interethnic differences in susceptibility to drug-induced arrhythmia. MethodsA randomized, double-blind crossover study was conducted in 24 (12 male and 12 female) Korean and 13 (seven male and six female) Caucasian subjects. After a 20 min infusion of quinidine (4 mg kg -1 ) or saline, the serum concentration of quinidine and the QT interval corrected by Bazett's formula (QTc) were monitored. The dynamic data were analyzed by means of a population modelling approach using NONMEM. ResultsThere were no statistical differences in the pharmacokinetic profiles of quinidine between ethnic groups. The QTc values in Caucasians were higher than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations and in female subjects. According to an Emax model E E E E Δ max , the population modelling approach revealed that E0 (ms) was related to gender (408 + [34*(1 -Sex)]; 1 for male and 0 for female), DEmax (ms) was related to ethnicity ((136* fETHN) + Cfemale: fETHN = 1 for Koreans and 1.26 for Caucasians; Cfemale was 106 only for Caucasian females), and EC50 was estimated to be 3.13 mm. ConclusionsThese results suggest that Korean subjects were less sensitive to quinidine-induced QT prolongation than Caucasian subjects, and that this trend was particularly true for females. Further population-based studies are merited to characterize more completely the ethnic differences in drug-induced QT prolongation between Asians and other ethnic groups.

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTcmodelling in a phase 1 study with oral rac-sotalol

“…Our data and other studies with potent QT prolonging drugs [27,31] suggest that women can be more sensitive to delay in cardiac repolarization induced by some drugs, as previously suggested by Woolsey's group [27], supported by in vitro experiments with quinidine [32] and with erythromycin [18]. Such a gender-based difference in sensitivity can be caused by hormonal effects, or differences in regard to the expression or activity of ion channels that regulate repolarization in the cardiomyocyte.…”

Genetic Polymorphism of Glutathione S-transferase T1 (GSTT1) and QT-Interval in Schizophrenia Patients

“…It is reported that quinidine concentrations in white British subjects tended to be lower than those in Nigerians, yet the quinidine-induced QTc increase was greater in white British subjects than in Nigerians (Olatunde and Price Evans 1982). Also, it is suggested that Korean subjects are less sensitive to quinidine-induced QTc prolongation than Caucasian subjects (Shin et al 2006). On the other hand, it is reported that, among normotensives, compared with whites, QTc is shorter in African-American and longer in Chinese, indicating that QTc parameter showed variation between different ethnic groups (Chapman et al 2000).…”

“…These determinants might lead to differences in the basic pattern and/or drug-induced QTc changes. There are relatively few data on interethnic differences in druginduced QT prolongation (Olatunde and Price Evans 1982;Shin et al 2006). It is reported that quinidine concentrations in white British subjects tended to be lower than those in Nigerians, yet the quinidine-induced QTc increase was greater in white British subjects than in Nigerians (Olatunde and Price Evans 1982).…”

Clinical ECG Assessment

“…It is also well documented that women are at higher risk for the development of proarrhythmias caused by drugs with an effect on cardiac repolarization, i.e., drugs that prolong the QTc interval (Bednar et al 2002;Ebert et al 2000;Makkar et al 1993). It would therefore seem reasonable to assume that women also react with a larger degree of QTc prolongation than men at the same plasma exposure of a drug, and there are a few documented examples thereof (Rodriguez et al 2001;Benton et al 2000;Shin et al 2007;). For drugs with only a mild effect on the QT interval, it has been difficult to demonstrate a gender difference in sensitivity for the drug-induced QTc prolongation.…”