Pharmacokinetic/pharmacodynamic modeling of the antitumor action of bispecific CD3/EpCAM antibody M701 in human colorectal cancer xenograft mice
10.16438/j.0513-4870.2020-0741
- VernacularTitle: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
- Author:
Ling SONG
1
;
Qing-yu YAO
1
;
Jun-sheng XUE
1
;
Si LI
2
;
Jing ZHANG
2
;
Dong-yang LIU
3
;
Tian-yan ZHOU
1
Author Information
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
- Publication Type:Research Article
- Keywords:
bispecific antibody;
human colorectal cancer xenograft mice;
pharmacokinetic/pharmacodynamic model;
modeling and simulation
- From:
Acta Pharmaceutica Sinica
2021;56(2):538-544
- CountryChina
- Language:Chinese
-
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.
