Pharmacokinetic/Pharmacodynamic Modeling of the Anti-Cancer Effect of Dexamethasone in Pancreatic Cancer Xenografts and Anticipation of Human Efficacious Doses

被引:3
|
作者
Yao, Ye [1 ]
Yao, Qingyu [1 ]
Fu, Yu [1 ]
Tian, Xiuyun [2 ]
An, Qiming [2 ]
Yang, Liang [1 ]
Su, Hong [1 ]
Lu, Wei [1 ]
Hao, Chunyi [2 ]
Zhou, Tianyan [1 ]
机构
[1] Peking Univ, Sch Pharmaceut Sci, Beijing Key Lab Mol Pharmaceut & New Drug Deliver, Dept Pharmaceut, Beijing 100191, Peoples R China
[2] Peking Univ Canc Hosp & Inst, Minist Educ Beijing, Key Lab Carcinogenesis & Translat Res, Dept Hepatopancreatobiliary Surg, Beijing 100142, Peoples R China
基金
中国国家自然科学基金;
关键词
pharmacokinetic/pharmacodynamic modeling; cancer; simulation; interspecies dose scaling; mathematical models; TUMOR-GROWTH INHIBITION; PLASMA; PHARMACOKINETICS; RESISTANT; SULPIRIDE; TRIAL; MICE;
D O I
10.1016/j.xphs.2019.10.035
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Dexamethasone (DEX), a synthetic glucocorticoid, exhibited anti-cancer efficacy in pancreatic xenografts derived from patient tumor tissue or cancer cell lines. The aim of this study was to establish pharmacokinetic/pharmacodynamic (PK/PD) models to quantitatively characterize the inhibitory effect of DEX on tumor growth as well as its discrepancy among 3 xenograft models. Data of tumor growth profiles were collected from a patient-derived xenograft (PDX) model in NOD/SCID mice and 2 cell line-derived (PANC-1 and SW1990) xenograft models in BALB/c nude mice. Empirical PK/PD models were developed to establish mathematical relationships between plasma concentration of DEX and tumor growth dynamics after integrating PK parameters extracted from literature. Drug effect in each model was well described by a linear inhibitory function with a potency factor of 4.67, 3.14, and 2.35 L/mg for PDX, PANC-1, and SW1990 xenograft, respectively. Human efficacious doses of DEX were preliminarily predicted through model-based simulation, and 60% tumor growth inhibition at clinical exposure corresponded to a daily dose range of 26-52 mg intravenously. This modeling work quantified the preclinical anti-cancer effect of DEX and demonstrated the feasibility of its medication in pancreatic cancer, which would be conductive to future translational research. (c) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
引用
收藏
页码:1169 / 1177
页数:9
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