摘要
目的建立具有特异性和高灵敏度的人血浆中托瑞米芬浓度测定的高效液相色谱-串联质谱(LC-MS/MS)检测方法,研究长半衰期药物托瑞米芬在健康人体的药代动力学特征并且采用截取的AUC_(0-72 h)来评价其生物等效性。方法用单中心、随机、开放、两周期、两序列、双交叉的试验设计,共入组56例健康受试者,空腹试验28例,餐后试验28例,分别单次口服试验制剂或参比制剂60 mg,用LC-MS/MS法测定人肝素钠血浆样品中托瑞米芬的浓度,用WinNonlin 7.0计算托瑞米芬药代动力学参数,以C_(max)和适当截取的AUC_(0-72 h)药物暴露量评价受试药物和参比药物的生物等效性。结果空腹组托瑞米芬受试制剂和参比制剂的药代动力学参数分别如下:C_(max)为(525.69±91.65)和(557.59±120.98)μg·L^(-1),t_(max)为2.50(1,4.5)和2.50(1.5,4.5)h,t_(1/2)为(65.32±35.65)和(59.69±31.18)h,AUC_(0-72 h)为(9261.71±1658.41)和(9550.77±1881.95)μg·h·L^(-1)。餐后组受试制剂和参比制剂托瑞米芬的主要药代动力学参数如下:C_(max)为(457.79±93.85)和(482.56±65.24)μg·L^(-1),t_(max)为4.50(2,12)和4.50(2,12)h,t_(1/2)为(55.08±22.00)和(56.56±28.73)h,AUC_(0-72 h)为(10896.95±2265.89)和(11554.71±2319.89)μg·h·L^(-1),空腹及餐后单次服用托瑞米芬受试制剂和参比制剂的C_(max)、AUC_(0-72 h)的几何均值比90%置信区间均落在80.00%~125.00%。结论LC-MS/MS检测方法特异性强、灵敏度高,用于托瑞米芬药代动力学和生物等效性研究可靠;空腹和餐后给药条件下,采用截取的AUC_(0-72 h)评价国产托瑞米芬受试药物和进口托瑞米芬参比药物主要药代动力学参数指标相近,具有生物等效性。
Objective To establish a high-performance liquid chromatography-tandem mass spectrometry(LC-MS/MS)method for the determination of toremifene concentration in human plasma with specificity and high sensitivity,and to study the pharmacokinetic characters of toremifene with long half-life in healthy subjects as well as its bioequivalence evaluated by truncated AUC_(0-72 h).Methods A single-center,randomized,open-label,two-period,two-sequence,and two-crossover trial design was used.A total of 56 healthy subjects were enrolled,of which 28 subjects were in fasting group,and 28 subjects in the fed group,with a single oral dose of test preparation or reference preparation 60 mg.Concentrations of toremifene in human heparin sodium plasma samples were quantitatively determined by LC-MS/MS.The pharmacokinetic parameters of toremifene were calculated by Win Nonlin 7.0,and the bioequivalence of the test drug and the reference drug was evaluated by C_(max)and appropriately truncated AUC_(0-72 h)of drug exposure.Results The pharmacokinetic parameters of test preparation and reference preparation of toremifene in fasting group were as follows:C_(max)(525.69±91.65)and(557.59±120.98)μg·h·L^(-1),t_(max)2.50(1,4.5)and 2.50(1.5,4.5)h,t_(1/2)(65.32±35.65)and(59.69±31.18)h,AUC_(0-72 h)(9261.71±1658.41)and(9550.77±1881.95)μg·h·L^(-1),respectively.The main pharmacokinetic parameters of test preparation and reference preparation toremifene in fed group were as follows:C_(max)(457.79±93.85)and(482.56±65.24)μg·h·L^(-1),t_(max)4.50(2,12)and 4.50(2,12)h,t_(1/2)(55.08±22.00)and(56.56±28.73)h,AUC_(0-72 h)(10896.95±2265.89)and(11554.71±2319.89)μg·h·L^(-1),respectively.The geometric mean ratios of C_(max)and AUC_(0-72 h)of the test preparation and the reference preparation for a single dose of toremifene in fasting and fed groups fell within 80.00%-125.00%.Conclusion The LC-MS/MS method has strong specificity and high sensitivity,and is reliable for the study of toremifene pharmacokinetics and bioequivalence.Under the fast
作者
温晓清
刘剑锋
陈学勤
伊金玲
WEN Xiao-qing;LIU Jian-feng;CHEN Xue-qin;YI Jin-ling(BE/PhaseⅠClinical Trial Center,the First Affiliated Hospital of Xiamen University,Xiamen 361003,Fujian Province,China;AccuBE PharmaTech Co.,Ltd,Xiamen 361003,Fujian Province,China)
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2023年第13期1943-1948,共6页
The Chinese Journal of Clinical Pharmacology
