药学学报, 2021, 56(2): 538-544
引用本文:
宋玲, 姚庆宇, 薛钧升, 李思, 张敬, 刘东阳, 周田彦. 药动学/药效学模型研究抗CD3/EpCAM双特异性抗体M701在人结肠癌异种移植小鼠中的抗肿瘤作用[J]. 药学学报, 2021, 56(2): 538-544.
SONG Ling, YAO Qing-yu, XUE Jun-sheng, LI Si, ZHANG Jing, LIU Dong-yang, ZHOU Tian-yan. Pharmacokinetic/pharmacodynamic modeling of the antitumor action of bispecific CD3/EpCAM antibody M701 in human colorectal cancer xenograft mice [J]. Acta Pharmaceutica Sinica, 2021, 56(2): 538-544.

药动学/药效学模型研究抗CD3/EpCAM双特异性抗体M701在人结肠癌异种移植小鼠中的抗肿瘤作用
宋玲1, 姚庆宇1, 薛钧升1, 李思2, 张敬2, 刘东阳3, 周田彦1
1. 北京大学药学院药剂学系, 分子药剂学与新释药系统北京市重点实验室, 北京 100191;
2. 武汉友芝友生物制药有限公司, 湖北 武汉 430075;
3. 北京大学第三医院药物临床试验机构, 北京 100191
摘要:
M701为抗分化簇3/表面上皮细胞黏附因子(cluster of differentiation 3/epithelial cell adhesion molecule,CD3/EpCAM)的双特异性抗体,拟用于治疗癌细胞腹腔转移引起的恶性腹水。本研究应用群体模型方法,构建M701在人结肠癌异种移植小鼠中的药动学/药效学(pharmacokinetic/pharmacodynamics,PK/PD)模型,定量描述和预测M701在人结肠癌异种移植小鼠中的抗肿瘤作用。基于人结肠癌异种移植小鼠单次给药后不同时间点血浆药物浓度,构建PK模型。基于人结肠癌异种移植小鼠(32只)在33天的肿瘤体积随时间变化曲线,构建对照组及给药组结肠癌小鼠的肿瘤生长模型。所有动物实验均严格遵守武汉友芝友公司动物实验福利规定。使用非线性混合效应模型(nonlinear mixed-effect modeling,NONMEM)构建M701药动学和肿瘤生长模型,并且进行模型验证评价。基于PK/PD模型,仿真不同给药方案下M701对肿瘤体积生长的抑制效果。选择二室模型描述M701静脉给药后人结肠癌异种移植小鼠体内的PK特征。使用Simeoni串联转移隔室模型描述在人结肠癌异种移植小鼠中M701药物浓度与肿瘤生长抑制之间的关系。肿瘤生长模型预测参数包括肿瘤生长特征参数λ0(0.212 d-1)、λ1(0.044 7 cm3·d-1)、药物效应参数k2(0.071 5 mL·ng-1·d-1)及肿瘤凋亡动力学参数k1(2×10-5 d-1)。可视化预测检测(visual predictive check,VPC)结果显示,PK模型及肿瘤生长模型的预测结果均能很好地拟合观测数据。PK/PD模型仿真结果显示,每6日静脉注射0.5 mg·kg-1及每3日静脉注射0.25 mg·kg-1可有效抑制小鼠肿瘤体积生长。本研究成功构建了M701在人结肠癌异种移植小鼠中的PK/PD模型,定量研究了M701在人结肠癌异种移植小鼠的抗肿瘤效果,为新化合物M701的进一步药物研发提供参考。
关键词:    双特异性抗体      人结肠癌异种移植小鼠      药动学/药效学模型      模拟与仿真     
Pharmacokinetic/pharmacodynamic modeling of the antitumor action of bispecific CD3/EpCAM antibody M701 in human colorectal cancer xenograft mice
SONG Ling1, YAO Qing-yu1, XUE Jun-sheng1, LI Si2, ZHANG Jing2, LIU Dong-yang3, ZHOU Tian-yan1
1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;
2. Wuhan YZY Biopharma Co., Ltd., Wuhan 430075, China;
3. Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
Abstract:
M701 is a bispecific CD3/EpCAM T-cell engager antibody for the treatment of malignant ascites. We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model to quantitatively describe and predict the antitumor effect of M701 in human colorectal cancer xenograft mice. We developed the M701 PK model based on plasma concentration data after i.v. administration. A tumor growth model for human colorectal cancer xenograft was developed to evaluate the antitumor effect of M701. We additionally simulated the inhibitory effect of M701 on tumor volume under different dose regimens based on a PK/PD model. A two-compartment model was developed to predict the PK in human colorectal cancer xenograft mice. The relationship between the M701 concentration and tumor growth inhibition was characterized by a combined Simeoni tumor growth/transit compartment model. The estimated pharmacodynamic parameters were related to the tumor growth characteristics λ0 (0.212 d-1) and λ1 (0.044 7 cm3·d-1), to the drug potency k2 (0.071 5 mL·ng-1·d-1), and to the kinetics of tumor cell death k1 (2×10-5 d-1). A model visual predictive check showed that both the PK model and the tumor growth model closely fit the observed data. Simulated tumor growth after administration of M701 (0.5 mg·kg-1 every 6 days and 0.25 mg·kg-1 every 3 days) could be effectively inhibited. This population PK/PD model of M701 provides insight into the antitumor effect of M701 and supports the further therapeutic development of M701.
Key words:    bispecific antibody    human colorectal cancer xenograft mice    pharmacokinetic/pharmacodynamic model    modeling and simulation   
收稿日期: 2020-07-12
DOI: 10.16438/j.0513-4870.2020-0741
基金项目: 国家自然基金青年科学基金项目(81903717).
通讯作者: 刘东阳,Tel/Fax:86-10-82665509,E-mail:liudongyang@vip.sina.com;周田彦,Tel/Fax:86-10-82801717,E-mail:tianyanzhou@vip.sina.com
Email: liudongyang@vip.sina.com;tianyanzhou@vip.sina.com
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