摘要
目的评价国产与原研硫酸氨基葡萄糖胶囊的餐后人体生物等效性。方法试验设计为单中心、随机、开放、单剂量、两制剂、三序列、三周期部分重复的交叉设计,试验药物为国产硫酸氨基葡萄糖胶囊伊索佳(受试制剂)和原研硫酸氨基葡萄糖胶囊维固力(参比制剂)。将健康受试者随机分为3组,每组均服药3个周期,但服用受试制剂(T)和参比制剂(R)的顺序不同,分别为TRR、RTR、RRT组。受试者分别在试验第1、4、7天进餐后30 min时口服试验药物。每次服药前1天晚餐后1~2 h(基线1)、服药前60 min内(基线2)、服药后15、30、45、60、90、120、150 min和3、4、5、6、8、10、14、16 h采集受试者外周静脉血各4 ml,离心后取血浆冻存。应用液相色谱-串联质谱法测定血浆样品中氨基葡萄糖浓度,计算血药浓度-时间曲线下面积[AUC,包括从0时至最后一个浓度可准确测定的样品采集时间t的AUC(AUC_(0-t))和从0时至无限时间(∞)的AUC(AUC_(0-∞))]和药峰浓度(Cmax)等主要药动学参数。由于氨基葡萄糖为人体内源性物质,采用减去服药前基线值(基线1和基线2的平均值)的方法对测得的氨基葡萄糖血药浓度进行校正。受试制剂与参比制剂AUC_(0-t)、AUC_(0-∞)和Cmax的几何均数比值(GMR)及其90%置信区间(CI)落在0.800~1.250范围内为等效。结果纳入试验的健康受试者共30例,男性20例,女性10例;年龄(31±7)岁,范围18~45岁。TRR、RTR、RRT组各10例。TRR组1例于第1周期服药后脱落,余29例完成试验。受试制剂与参比制剂未经基线校正的AUC_(0-t)、AUC_(0-∞)、Cmax的GMR(90%CI)分别为0.985(0.941~1.031)、1.014(0.961~1.070)和0.937(0.827~1.062),经基线校正的AUC_(0-t)、AUC_(0-∞)、Cmax的GMR(90%CI)分别为0.977(0.923~1.035)、0.976(0.922~1.032)和0.932(0.817~1.063),均落在等效范围内(0.800~1.250)。试验期间3组受试者均未发生与试验药物相关的不良事件。结论国产与原研硫酸氨基葡萄糖胶囊餐后服用情况下具有生物等效性,安全性良好。
Objective To evaluate the postprandial bioequivalence of domestic and original glucosamine sulfate capsules in Chinese healthy volunteers.Methods The trial was a single-center,randomized,open-label,single-dose,2-preparation,3-sequence,3-period,partially repeated crossover design.The trialed drugs were domestic glucosamine sulfate capsules Yisuojia(test preparation)and original glucosamine sulfate capsules Viartril-(reference preparation).Healthy subjects were randomly divided into 3 groups,each group took medicine in 3 periods,but the order of taking test preparation(T)and reference preparation(R)was different,which were TRR,RTR and RRT groups.The healthy volunteers in the TRR,RTR,and RRT groups received the trialed drugs orally 30-minutes after diet supply on day 1,4,and 7,respectively.Peripheral venous blood samples 4-ml were collected at 1-2 hours after dinner the day before medication(baseline 1),within 60-minutes before medication(baseline 2),and 15,30,45,60,90,120,and 150-minutes and 3,4,5,6,8,10,14,and 16-hours after medication,respectively.Plasma was collected after centrifugation,frozen,and stored.Liquid chromatography-tandem mass spectrometry was used for the determination of glucosamine concentrations in plasma samples and main pharmacokinetic parameters such as the area under the concentration-time curve(AUC),including areas from time zero(pre-dose)to the last measurable concentration(AUC_(0-t))and extrapolated to infinite time(AUC_(0-∞)),and peak concentration(Cmax)were calculated.Because glucosamine was an endogenous substance in humans,the measured blood concentration of glucosamine was corrected by subtracting the baseline value before medication(the average of baseline 1 and baseline 2).The test and reference preparations were equivalent when the geometric mean ratios(GMR)and their 90%confidence intervals(CI)for AUC_(0-t),AUC_(0-∞),and Cmax all ranged from 0.800 to 1.250.Results A total of 30-healthy volunteers were enrolled in the study,including 20 males and 10 females,aged(31±7)years with a range of 18-45 years.Ten volunteers were included in each TRR,RTR,and RRT group.One volunteer fell off in the TRR group after the first period of medication and the remaining 29 volunteers completed the trial.The baseline uncorrected GMR(90%CI)of AUC_(0-t),AUC_(0-∞),and Cmax for the test and the reference preparations were 0.985(0.941-1.031),1.014(0.961-1.070),and 0.937(0.827-1.062),respectively;the baseline corrected GMR(90%CI)of AUC_(0-t),AUC_(0-∞),and Cmax of the test and the reference preparations were 0.977(0.923-1.035),0.976(0.922-1.032),and 0.932(0.817-1.063),respectively,which all fell within the equivalence range(0.800-1.250).During the trial,no adverse events related to the trialed drugs occurred in the 3 groups.Conclusion Domestic glucosamine sulfate capsules were bioequivalent to the original when taken after diet and had a good safety profile.
作者
荆珊
王欣
杨克旭
刘文芳
李静
谭莉
所伟
鲁春艳
林阳
Jing Shan;Wang Xin;Yang Kexu;Liu Wenfang;Li Jing;Tan Li;Suo Wei;Lu Chunyan;Lin Yang(Clinical Pharmacology Centre,Beijing Anzhen Hospital,Capital Medical University,Beijing,100029,China;Clinical Pharmacology Department,Zhejiang Hisun Pharmaceutical Co.,Ltd,Zhejiang Province,Taizhou 318000,China)
出处
《药物不良反应杂志》
CSCD
2021年第3期113-119,共7页
Adverse Drug Reactions Journal
基金
“重大新药创制”科技重大专项(2017XZ09304017)。
作者简介
通信作者:林阳,Email:linyang3623@163.com。
