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

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)。试验组与对照组受试者总体AE发生率[89.5%(34/38)比87.2%(34/39)]、与试验药物可能相关AE发生率[86.8%(33/38)比79.5%(31/39)]差异均无统计学意义(均P>0.05)。AE严重程度仅试验组有1例为3级且经评估与药物无关,余为1~2级,以1级占绝大多数。试验组和对照组抗药抗体阳性率差异无统计学意义[10.5%(4/38)比10.3%(4/39),P>0.05)。抗药抗体阳性者中和抗体检测均为阴性。结论WBP264与Avastin®的药代动力学和安全性相似。

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 after administration to evaluate the im‑munogenicity of the drug.Results A total of 78 subjects were recruited,39 in the trial group and 39 in the control group.In the trial group,2 cases withdrew from the trial(1 case did not take the drug and 1 case withdrew for personal reason after taking the drug).Seventy‑seven cases were in the safety analysis set and 76 cases in the pharmacokinetic analysis set.The differences in age,height,weight,and body mass index between the 2 groups were not significant(all P>0.05).The plasma concentration‑time curves of bevaci‑zumab between the trial group and the control group were similar.The geometric mean ratios(90%CI)of AUC_(0‑t),AUC_(0‑∞),and C_(max) were 1.04(0.98-1.10),1.03(0.98-1.10),and 1.09(1.03-1.14),respectively.The dif‑ferences in the incidence of overall AEs[89.5%(34/38)vs.87.2%(34/39)]and the incidence of AEs possibly re‑lated to the trial drug[86.8%(33/38)vs.79.5%(31/39)]between the trial group and the control group were not significant(all P>0.05).Only one case of AE in the trial group was grade 3 in severity and was assessed as being not related to the drug,and the rest were grade 1‑2,with grade 1 AEs accounting for the vast majority.The difference in the positive rate of anti‑drug antibody between the trial group and the control group was not significant[10.5%(4/38)vs.10.3%(4/39),P>0.05].The neutralizing antibody test was negative in the patients with positive anti‑drug antibody.Conclusion The pharmacokinetics and safety of WBP264 and Avastin®are similar.