仿制与原研贝伐珠单抗药代动力学和安全性比对的Ⅰ期临床试验  

Phase I clinical trial of pharmacokinetics and safety comparison between the generic and the original bevacizumab

作　　者：任秀华[1] 余恒毅 方一念 张冬林[1] 陈倩[1] 雷永芳[1] 刘东[1] 刘喆隆[2] Ren Xiuhua;Yu Hengyi;Fang Yinian;Zhang Donglin;Chen Qian;Lei Yongfang;Liu Dong;Liu Zhelong(Phase I Clinical Trial Unit,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China;Department of Endocrinology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Branch of National Clinical Research Center for Metabolic Diseases,Wuhan 430030,China)

机构地区：[1]华中科技大学同济医学院附属同济医院Ⅰ期临床试验研究室,武汉430030 [2]华中科技大学同济医学院附属同济医院内分泌科,国家代谢性疾病临床医学研究中心分中心,武汉430030

出　　处：《药物不良反应杂志》2022年第6期300-307,共8页Adverse Drug Reactions Journal

基　　金：国家科技重大专项(2017ZX09304022)。

摘　　要：目的比较仿制贝伐珠单抗注射液WBP264与原研贝伐珠单抗注射液Avastin®在健康男性志愿者单次静脉给药的药代动力学和安全性。方法研究设计为随机、双盲、单剂量、平行、对照的Ⅰ期临床试验。将公开招募的健康男性受试者随机分入试验组(静脉输注WBP264)与对照组(静脉输注Avastin®),给药剂量为3 mg/kg。给药前30 min内、给药开始后45 min、给药结束即刻、给药后2.5、3.5、5.5、9.5、13.5、24、48 h和第5、8、15、22、29、36、43、57、71、85和99天采集受试者外周静脉血,采用酶联免疫吸附法测定血药浓度,绘制血药浓度-时间曲线及其半对数图,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‑∞))]、血药峰浓度(C_(max))、达峰时间(T_(max))、血浆消除半衰期、清除率和表观分布容积等药代动力学参数。试验组与对照组AUC_(0‑t)、AUC_(0‑∞)和C_(max)几何均值比值的90%置信区间(CI)介于0.80~1.25,表明WBP264与Avastin®药代动力学相似。在给药观察期间及每次采血随访时,对受试者进行体格、生命体征、心电图、实验室检查,记录不良事件(AE)发生情况并进行AE严重程度分级以及AE与试验药物相关性评价。给药前和给药后第8、15、29、43、71和99天进行抗药抗体及其中和抗体检测,评估药物的免疫原性。结果纳入试验的受试者为78例,试验组和对照组各39例。试验组有2例退出试验(未给药和给药后因个人原因退出各1例),安全性分析集77例,药代动力学分析集76例。2组受试者年龄、身高、体重和体重指数差异均无统计学意义(均P>0.05)。试验组与对照组贝伐珠单抗血药浓度-时间曲线变化趋势相似,AUC_(0‑t)、AUC_(0‑∞)、C_(max)的几何均值比值(90%CI)分别为1.04(0.98~1.10)、1.03(0.98~1.10)、1.09(1.03~1.14)。试验组与�Objective To compare the pharmacokinetics and safety of single intravenous injec‑tion of the generic bevacizumab injection WBP264 and the original bevacizumab injection Avastin®in healthy male volunteers.Methods The study was designed as a randomized,double‑blind,single dose,parallel,and controlled phase I clinical trial.Healthy male volunteers who were recruited publicly were randomized into the trial group(intravenous infusion of WBP264)and the control group(intravenous infusion of Avastin®),and the dose was 3 mg/kg.Peripheral venous blood was collected within 30 minutes before administration,45 minutes after onset of the administration,immediately after finishing the administration,2.5,3.5,5.5,9.5,13.5,24,48 hours and on the 5th,8th,15th,22nd,29th,36th,43rd,57th,71st,85th,and 99th days after the administration.The plasma concentration was measured by enzyme‑linked immunosor‑bent assay,the plasma concentration-time curve and its semilogarithmic plot were plotted,and the pharmaco‑kinetic parameters such as the area under the plasma concentration-time curve[including AUC from time zero to the time of the last quantifiable concentration(AUC0-t)and AUC from time zero to infinity(AUC_(0‑∞))],peak concentration(C_(max)),time to peak(T_(max)),plasma elimination half‑life(t1/2),clearance rate(CL),and ap‑parent volume of distribution(Vd)were calculated.When the 90%confidence intervals(CI)of the geometric mean ratio of AUC_(0‑t),AUC_(0‑∞),and C_(max) between the trial group and the control group were between 0.80-1.25,it indicated that pharmacokinetics of WBP264 and Avastin®were similar.The physical examina‑tion,vital signs detection,electrocardiogram,and laboratory tests were performed on the subjects,the occur‑rence of adverse events(AEs)and the severity classification were recorded,and correlation between the AEs and the trial drug was evaluated.The anti‑drug antibody and its neutralizing antibody were detected before administration and on the 8th,15th,29th,43rd,71st,and 99th days afte

关 键 词：血管内皮生长因子 单克隆抗体 贝伐珠单抗 等效性试验 药代动力学 安全性 

分 类 号：R969[医药卫生—药理学]