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Pharmacokinetic/pharmacodynamic modeling of the antitumor action of bispecific CD3/EpCAM antibody M701 in human colorectal cancer xenograft mice
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Ling SONG1, Qing-yu YAO1, Jun-sheng XUE1, Si LI2, Jing ZHANG2, Dong-yang LIU*, 3, Tian-yan ZHOU*, 1
Acta Pharmaceutica Sinica | 2021, 56(2) : 538 - 544
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Acta Pharmaceutica Sinica | 2021, 56(2): 538-544
Original Articles
Pharmacokinetic/pharmacodynamic modeling of the antitumor action of bispecific CD3/EpCAM antibody M701 in human colorectal cancer xenograft mice
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Ling SONG1, Qing-yu YAO1, Jun-sheng XUE1, Si LI2, Jing ZHANG2, Dong-yang LIU*, 3, Tian-yan ZHOU*, 1
Affiliations
  • 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
Published: 2021-02-12 doi: 10.16438/j.0513-4870.2020-0741
Outline
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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.

bispecific antibody  /  human colorectal cancer xenograft mice  /  pharmacokinetic/pharmacodynamic model  /  modeling and simulation
Ling SONG, Qing-yu YAO, Jun-sheng XUE, Si LI, Jing ZHANG, Dong-yang LIU, Tian-yan ZHOU. 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 . DOI: 10.16438/j.0513-4870.2020-0741
Year 2021 volume 56 Issue 2
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Article Info
doi: 10.16438/j.0513-4870.2020-0741
  • Receive Date:2020-07-12
  • Online Date:2025-12-18
  • Published:2021-02-12
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History
  • Received:2020-07-12
  • Revised:2020-09-12
Funding
Affiliations
    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
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表12种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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