基于食蟹猴体内药动学的PD-1单抗GLS-010的人体药动学特征预测研究  

Prediction of PD-1 monoclonal antibody human pharmacokinetic characteristics based on PK in cynomolgus monkeys

作　　者：徐艳军 韩子军 王靓 杨芳 娄蓓蕾 闫少羽 朱吉满 白莉惠 高勇[4] XU Yanjun;HAN Zijun;WANG Liang;YANG Fang;LOU Beilei;YAN Shaoyu;ZHU Jiman;BAI Lihui;GAO Yong(Shanghai East Hospital Postgraduate Training Base,Jinzhou Medical University,Shanghai 200120,China;Liaocheng Vitiligo Hospital,Liaocheng 252000,China;Guangzhou Yuheng Biological Co.,LTD.,Beijing 101300,China;East Hospital Affiliated to Tongji University,Shanghai 200120,China)

机构地区：[1]锦州医科大学上海市东方医院研究生培养基地,上海200120 [2]聊城市白癜风医院,山东聊城252000 [3]广州誉衡生物有限公司,北京101300 [4]同济大学附属东方医院,上海200120

出　　处：《中国药理学与毒理学杂志》2025年第2期109-117,共9页Chinese Journal of Pharmacology and Toxicology

摘　　要：目的采用新型程序性细胞死亡蛋白1(PD-1)单抗(GLS-010)在食蟹猴体内的药动学(PK)数据构建群体药动学(PopPK)模型,预测GLS-010在人体的PK特征。方法食蟹猴58只,其中18只食蟹猴随机分为3组,分别单次静脉滴注GLS-0102,6和18 mg·kg^(-1),其余40只食蟹猴随机分为4组,分别多次静脉滴注给予GLS-0100,5,25和100 mg·kg^(-1),每周1次(qw),连续5次。分别于给药前和给药后进行血样采集,采用ELISA检测食蟹猴血清GLS-010浓度,超敏电化学发光法测定食蟹猴血清中抗药抗体(ADA)浓度,获得GLS-010在食蟹猴体内的PK数据,绘制GLS-010在食蟹猴体内的药-时曲线,并通过非房室分析进行PopPK模型的构建,通过拟合优度图和可视化预测检验进行评价,运用构建的PopPK模型进行人体PK特征的预测,最后与实际Ⅰ期临床研究结果进行比较验证。结果构建的PopPK模型预测PK的结果与实际Ⅰ期临床研究结果具有较高的一致性,能较好地预测GLS-010在1 mg·kg^(-1)每2周1次(q2w),4 mg·kg^(-1)(q2w),240 mg(q2w),240 mg每3周1次(q3w)和10 mg·kg^(-1)(q2w)给药模式下的人体PK特征,预测的GLS-010最大血药浓度(Cmax)分别为24.8,99.1,85.0,85.0和247.8 mg·L^(-1),药物浓度-时间曲线下面积AUC_(0-336 h)分别为4902.0,20060.0,17147.7,22145.7(AUC_(0-504 h))和50817.6 mg·h·L^(-1)。相应给药模式下的安全范围比分别为47.3,11.6,13.5,10.5和4.6。在预测的Cmax、平均血药浓度(C_(avg))和最小血药浓度(C_(min))下稳态受体占有率(RO_(ss))分别为38.8%,72.7%,69.4%,64.1%,87.2%;29.1%,63.8%,60.0%,49.8%,82.1%;21.9%,55.5%,51.3%,36.3%,76.7%。结论该PopPK模型能较好预测不同给药模式下GLS-010的人体PK特征,与实际Ⅰ期临床研究结果一致性较高,可为首次人体研究安全有效剂量的选择提供参考依据。OBJECTIVE To establish a population pharmacokinetic(PopPK)model to predict the PK characteristics of GLS-010 in humans.METHODS Fifty-eight cynomolgus monkeys were used,18 of which were randomly divided into three groups and received a single intravenous infusion of GLS-010 at doses of 2,6,and 18 mg·kg^(-1),respectively.The rest were randomly assigned to four groups and received multiple intravenous infusions of GLS-010 at doses of 0,5,25,and 100 mg·kg^(-1),respectively,once a week(quaque week,qw)for five consecutive weeks.Blood samples were collected before and after ad_(min)istration.The concentrations of GLS-010 in the monkey serum were measured using a validated enzyme-linked immunosorbent assay,while those of anti-drug antibodies(ADA)in the cynomolgus monkey serum were deter_(min)ed by ultra-sensitive electrochemiluminescence immunoassay.The PK data on GLS-010 in cynomolgus monkeys was obtained,and the drug-time curves were plotted.A PopPK model was constructed using non-compartmental analysis and evaluated by goodness-of-fit plots and visual predictive checks.The constructed PopPK model was used to predict the PK characteristics in humans,which were finally compared with actual PhaseⅠclinical study results for validation.RESULTS The predictive results of the PopPK model were highly consistent with the actual PhaseⅠclinical study results.The model was able to predict the human PK characteristics under various dosing regimens,including 1 mg·kg^(-1)quaque 2 weeks(q2w),4 mg·kg^(-1)(q2w),240 mg(q2w),240 mg(q3w),and 10 mg·kg^(-1)(q2w).The predicted maximum plasma concentrations(Cmax)were 24.8,99.1,85.0,85.0,and 247.8 mg·L^(-1),respectively,and the AUC_(0-336 h)was 4902.0,20060.0,17147.7,22145.7(AUC_(0-504 h)),and 50817.6 mg·h·L^(-1),respectively.The safety risks for the corresponding dosing regimens were 47.3,11.6,13.5,10.5,and 4.6,respectively.The predicted receptor occupancy at steady state(RO_(ss))at Cmax,average plasma concentration(C_(avg)),and_(min)imum plasma concentration(C_(min))were 38.8%,72.

关 键 词：程序性细胞死亡蛋白1 人体药动学 单克隆抗体 

分 类 号：R969[医药卫生—药理学]