Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.
Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.
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DOI：
10.1002/bdd.1850
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发表时间：
2013-09
影响因子：
2.1
通讯作者：
Sun D
中科院分区：
文献类型：
--
作者：
Zhang T;Li Y;Zou P;Yu JY;McEachern D;Wang S;Sun D
凋亡抑制蛋白（inhibitors of apoptosis proteins，IAPs）是一类在肿瘤中过度表达或失调的关键凋亡调节因子。SM-406/AT-406是一种有效的、选择性的Smac小分子模拟物，可拮抗凋亡抑制蛋白（IAP）。开发了一种基于生理学的药代动力学和药效学（PBPK-PD）模型，用于预测SM-406在荷人乳腺癌异种移植物小鼠模型中的组织浓度-时间曲线、肿瘤中相关癌蛋白水平以及肿瘤生长抑制。在用于药代动力学表征的全身生理药代动力学（PBPK）模型中，使用充分搅拌（灌注速率限制）模型描述SM-406在肺、心脏、肾脏、肠、肝脏和脾脏中的药代动力学，并使用扩散速率限制（渗透性限制）模型描述肿瘤。开发了药效学（PD）模型，以将SM-406在肿瘤中的浓度与cIAP 1降解、半胱天冬酶原8降低、CL-PARP蓄积和肿瘤生长抑制相关联。PBPK-PD模型很好地描述了实验药代动力学数据、药效学生物标志物反应和肿瘤生长。该模型可用于临床预测肿瘤及血浆SM-406浓度。
The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration–time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic.
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影响因子：
7.3
作者：
Cai Q;Sun H;Peng Y;Lu J;Nikolovska-Coleska Z;McEachern D;Liu L;Qiu S;Yang CY;Miller R;Yi H;Zhang T;Sun D;Kang S;Guo M;Leopold L;Yang D;Wang S
通讯作者：
Wang S
影响因子：
64.5
作者：
Du, CY;Fang, M;Wang, XD
通讯作者：
Wang, XD
影响因子：
64.8
作者：
Ponder, BAJ
通讯作者：
Ponder, BAJ
影响因子：
64.8
作者：
Liu, ZH;Sun, CH;Fesik, SW
通讯作者：
Fesik, SW
影响因子：
3.9
作者：
Salphati, Laurent;Wong, Harvey;Wallin, Jeffrey J.
通讯作者：
Wallin, Jeffrey J.