ω-3-脂肪酸乙酯在中国健康受试者中单次和多次给药的药代动力学研究  

Pharmacokinetics of single and multiple doses of omega-3-acid ethyl esters in healthy Chinese subjects

作　　者：荆珊[1] 谭莉[1] 杨克旭[1] 刘文芳[1] 鲁春艳[1] 林阳[1] JING Shan;TAN Li;YANG Ke-xu;LIU Wen-fang;LU Chun-yan;LIN Yang(Clinical Pharmacology Centre,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China)

机构地区：[1]首都医科大学附属北京安贞医院临床药理中心,北京100029

出　　处：《中国临床药理学杂志》2021年第10期1226-1230,共5页The Chinese Journal of Clinical Pharmacology

基　　金：国家科技重大专项基金资助项目(2017ZX09304017)。

摘　　要：目的评价单次和多次口服ω-3-脂肪酸乙酯在中国受试者中的药代动力学(PK)特征以及安全性和耐受性。方法本研究采用单中心、单次和多次给药、开放试验设计,共入组健康受试者12例。第1天单次口服2 g,之后是3 d洗脱期;第4~9天多次口服2 g,每日2次;第10天仅早晨口服2 g。按计划的PK采血时间点采集全血样本(每份6 mL),使用经过验证的方法测定二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)的血浆浓度。通过实测浓度减去基线期(给药前)浓度,对血药浓度实测值进行调整。确定原始浓度和基线值校正浓度-时间曲线,并用于计算PK参数。结果单次给药时基线校正EPA的AUC0-24 h、AUC0-48 h、Cmax的几何均数分别为461.996 h·μg·mL^(-1),703.14 h·μg·mL^(-1)和42.32μg·mL^(-1),中位Tmax为6.0 h。单次给药时基线校正DHA的AUC0-24 h、AUC0-48 h、Cmax的几何均数分别为209.38 h·μg·mL^(-1),307.82 h·μg·mL^(-1)和29.28μg·mL^(-1),中位Tmax为4.0 h。多次给药时基线校正EPA的AUC0-24 h和Cmax的几何均数分别为1643.46 h·μg·mL^(-1)和107.72μg·mL^(-1),中位Tmax为4.0 h。多次给药时基线校正DHA的AUC0-24h和Cmax的几何均数分别为837.84 h·μg·mL^(-1)和69.59μg·mL^(-1),中位Tmax为4.0 h。12例受试者中有4例(33.3%)受试者报告了5例次不良事件(AE),包括低血压(16.7%)、高三酰甘油血症(8.3%)、高尿酸血症(8.3%)和血肌酸磷酸激酶升高(8.3%)。经评估没有与药物相关的AE。与同品种在白人的PK参数进行分析,表明在中国健康受试者中进行的PUFA1001 PK研究的ω-3-脂肪酸乙酯EPA和DHA的AUC和Cmax与TEVA进行的BE研究和Steffen进行的PK研究参数相似。结论 Omacor多次给药的PK特征与单次给药相似,不同种族(包括白人和中国健康志愿者)之间的差异无统计学意义。Objective To investigate the pharmacokinetics(PK), the safety and tolerability of omega-3-acid ethyl esters after administration of single and multiple oral doses of omega-3-acid ethyl esters in healthy Chinese subjects.Methods This study was a single center, single and multiple dose, open-label PK study. One group of subjects(n=12) was studied. Day 1: one single oral dose of 2 g followed by a washout of three days. Day 4-9: multiple dosing of 2 g twice daily. Day 10: morning dose only of 2 g. Whole blood samples(6 mL each) were obtained for determination of eicosapentaenoicacid(EPA) and docosahexaenoic acid( DHA) plasma concentrations at the scheduled PK time points. Plasma concentrations of EPA and DHA were determined by validated methods. The observed plasma concentrations were adjusted by subtracting baseline( predose) concentrations from the observed concentrations. Raw and baseline corrected concentration-time profiles were determined and used to calculate pharmacokinetics parameters. Results The geometric mean of AUC0-24 h,AUC0-48 h,Cmaxfor baseline-corrected EPA for single dose were 461. 996 h · μg · mL^(-1),703. 14 h·μg·mL^(-1),42. 32 μg·mL^(-1),and the median Tmaxwas 6. 0 h. The geometric mean of AUC0-24 h,AUC0-48 h,Cmax for baseline-corrected DHA for single dose were 209. 38 h·μg·mL^(-1),307. 82 h·μg·mL^(-1),29. 28 μg·mL^(-1),and the median Tmaxwas 4. 0 h. The geometric mean of AUC0-24 h,Cmaxfor baseline-corrected EPA for multiple doses were 1643. 46 h·μg·mL^(-1),107. 72 μg·mL^(-1),and the median Tmaxwas 4. 0 h. The geometric mean of AUC0-24 h,Cmaxfor baseline-corrected DHA for multiple doses were 837. 84 h·μg·mL^(-1),69. 59 μg·mL^(-1),and the median Tmaxwas 4. 0 h. Of 12 subjects,5 adverse events reported in 4( 33. 3%) subjects,including hypotension( 16. 7%),hypertriglyceridaemia( 8. 3%),hyperuricaemia( 8. 3%) and blood creatine phosphokinase increased( 8. 3%). None of the AEs was assessed as drug-related AE. Analysis of the PK parameters of the same species in the white popu

关 键 词：ω-3-脂肪酸乙酯 药代动力学 安全性 耐受性 

分 类 号：R97[医药卫生—药品]