Wei Wang1, Hong-Jie Qian2, Liang Xin2, Meng-Qi Zhang2, Dong-Ying Lu3, Jie-Mei Jin2, Gang-Yi Liu2, Jing-Ying Jia2, Hong-Chao Zheng4, Chen Yu2, Yi-Ping Wang3, Fu Zhu5, Yun Liu6. 1. Emergency Ward, Shanghai Xuhui Central Hospital and Zhongshan-Xuhui Hospital, Fudan University and Shanghai Clinical Center, Chinese Academy of Science, Shanghai, China. 2. Central Laboratory, Shanghai Xuhui Central Hospital and Zhongshan-Xuhui Hospital, Fudan University and Shanghai Clinical Center, Chinese Academy of Science, Shanghai, China. 3. Department of Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. 4. Department of Cardiology, Shanghai Xuhui Central Hospital and Zhongshan-Xuhui Hospital, Fudan University and Shanghai Clinical Center, Chinese Academy of Science, Shanghai, China. 5. Department of Cardiology, Shanghai Xuhui Central Hospital and Zhongshan-Xuhui Hospital, Fudan University and Shanghai Clinical Center, Chinese Academy of Science, Shanghai, China. zhufu@xh.sh.cn. 6. Central Laboratory, Shanghai Xuhui Central Hospital and Zhongshan-Xuhui Hospital, Fudan University and Shanghai Clinical Center, Chinese Academy of Science, Shanghai, China. yliu@shxh-centerlab.com.
Abstract
BACKGROUND: Sulcardine sulfate is a novel antiarrhythmic agent with mechanism of action as a multi-ion channel blocker. Preclinical studies in animal models have demonstrated that sulcardine sulfate is efficacious in atrial and ventricular arrhythmias, and consequently, leads to the prevention of sudden cardiac death. OBJECTIVES: This study was conducted in healthy Chinese male subjects to investigate the pharmacokinetic profile and safety of sulcardine sulfate after repeated oral dose administration at 200, 400, and 800 mg for 5 days. METHODS: Thirty-three male subjects were enrolled in this study. In the multiple dose phase, sulcardine sulfate was administered orally twice at the interval of q12 h since day 3. Sulcardine sulfate plasma concentration was determined using a validated LC-MS/MS method. Safety was assessed using clinical evaluation and AE monitoring. RESULTS: In this repeated dose study, pharmacokinetic parameters (C max, AUC(0-t), and C ss_av) increased with the increase in dose (the dose ratio of the three cohorts was 1:2:4, while the ratio of C max and AUC(0-t) at day 1 was around 1:4:9 and 1:4:6, respectively), but in a non-linear fashion. The accumulation ratio at steady state (AR) of 200, 400, and 800 mg dose level was 1.18, 1.69, and 2.13, respectively, indicating that sulcardine sulfate has a modest accumulation upon repeated dose administration. Monitoring of pre-dose plasma concentrations on days 6, 7, and 8 for each dose level indicated that steady state was achieved at day 6 after three-day repeated dosing. CONCLUSIONS: Pharmacokinetic characteristics of sulcardine sulfate were shown to be non-linear, with the modest accumulation upon repeated dosing, and sulcardine sulfate was safe and well tolerated.
BACKGROUND: Sulcardine sulfate is a novel antiarrhythmic agent with mechanism of action as a multi-ion channel blocker. Preclinical studies in animal models have demonstrated that sulcardine sulfate is efficacious in atrial and ventricular arrhythmias, and consequently, leads to the prevention of sudden cardiac death. OBJECTIVES: This study was conducted in healthy Chinese male subjects to investigate the pharmacokinetic profile and safety of sulcardine sulfate after repeated oral dose administration at 200, 400, and 800 mg for 5 days. METHODS: Thirty-three male subjects were enrolled in this study. In the multiple dose phase, sulcardine sulfate was administered orally twice at the interval of q12 h since day 3. Sulcardine sulfate plasma concentration was determined using a validated LC-MS/MS method. Safety was assessed using clinical evaluation and AE monitoring. RESULTS: In this repeated dose study, pharmacokinetic parameters (C max, AUC(0-t), and C ss_av) increased with the increase in dose (the dose ratio of the three cohorts was 1:2:4, while the ratio of C max and AUC(0-t) at day 1 was around 1:4:9 and 1:4:6, respectively), but in a non-linear fashion. The accumulation ratio at steady state (AR) of 200, 400, and 800 mg dose level was 1.18, 1.69, and 2.13, respectively, indicating that sulcardine sulfate has a modest accumulation upon repeated dose administration. Monitoring of pre-dose plasma concentrations on days 6, 7, and 8 for each dose level indicated that steady state was achieved at day 6 after three-day repeated dosing. CONCLUSIONS: Pharmacokinetic characteristics of sulcardine sulfate were shown to be non-linear, with the modest accumulation upon repeated dosing, and sulcardine sulfate was safe and well tolerated.
Authors: Donglin Guo; Que Liu; Tengxian Liu; Gary Elliott; Mireille Gingras; Peter R Kowey; Gan-Xin Yan Journal: J Cardiovasc Pharmacol Date: 2011-01 Impact factor: 3.105