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.
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Acknowledgments
The authors sincerely thank the healthy volunteers who participated in the clinical study.
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Funding
This work was supported by grants from the Ministry of Science and Technology of China (No. 2010ZX09502-003) and the Shanghai Committee of Science and Technology, China (No. 15DZ2291800).
Conflict of interest
None of the authors (Wei Wang, Hong-jie Qian, Liang Xin, Meng-qi Zhang, Dong-ying Lu, Jie-mei Jin, Gang-yi Liu, Jing-ying Jia, Hong-chao Zheng, Chen Yu, Yi-ping Wang, Fu Zhu, and Yun Liu) have any conflicts of interest to report.
Ethical Approval
All procedures in this study were in accordance with the 1964 Helsinki declaration (and its amendments). The study protocol was approved by the Independent Ethics Committee of Shanghai Xuhui Central Hospital, Shanghai, China.
Informed Consent
All subjects provided written informed consent prior to start of study-related procedures.
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Wang, W., Qian, Hj., Xin, L. et al. Multiple Dose Pharmacokinetics and Safety of Sulcardine Sulfate in Healthy Chinese Male Subjects: An Open-Label Phase I Clinical Study. Eur J Drug Metab Pharmacokinet 42, 593–599 (2017). https://doi.org/10.1007/s13318-016-0370-1
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DOI: https://doi.org/10.1007/s13318-016-0370-1