PO.ET07.02 · 实验与分子治疗
一系列抗癌药物在免疫缺陷雌性NOD scid gamma小鼠中的药代动力学
Pharmacokinetics of a series of anticancer agents in immunodeficient female NOD scid gamma mice
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：我们旨在表征一系列20种抗癌药物在高度免疫缺陷雌性NOD scid gamma（NSG）小鼠中的临床前药代动力学（PK），以为NCI PDX开发和试验中心研究网络（PDXNet）正在研究的药物提供清除率和暴露数据。
方法：将该系列20种抗癌药物（CDK4/6、PI3K-beta/PI3K-delta、ATR、MEK1/2、PI3K、微管、EZH2、BCL-2、PARP、组蛋白去乙酰化酶、gamma-分泌酶、FGFR、SHP2和ERK1/2的抑制剂，以及一种SMAC模拟物）通过IV、PO或IP途径给予雌性NSG小鼠，以表征PDX疗效测试所用条件下的血浆暴露。分别在给药后15、30、60、120、240、360、480和1440分钟采集系列血浆样本。使用验证的LC-MS/MS检测定量药物浓度。使用非房室分析计算PK参数。
结果：确定了每种药物的PK，清除率和半衰期值列于下表中。Navitoclax的PK指标无法计算。由于代谢率较高，小鼠表现出更快的PK过程。它们通常具有比人类更短的半衰期和更高的体重标准化清除率。Copanlisib、Navitoclax和Trametinib是例外。
结论：这些PK数据对于理解PDXNet所研究药物的抗肿瘤活性至关重要，并将有助于研究者开发用于临床前安全性研究的新方法学，为人体临床试验做准备。
药代动力学分析 药物 清除率（L/hr*kg） 半衰期（小时） abemaciclib 1.32 10.99 AZD8186 4 2.42 BAY-1895344 1.77 4.72 birinapant 4.19 8.47 cobimetinib 0.76 21.9 copanlisib 9.42 2.78 docetaxel 1.71 1.17 EPZ-011989 1.13 2.06 niraparib 1.25 10.11 olaparib 4.63 3.44 panobinostat 241.55 3.80 RO4929097 1.01 4.2 rogaratinib 0.46 3.86 romidepsin 6.2 14.38 selumetinib 0.77 5.91 SHP099 0.35 55.12 talozoparib 0.295 4.26 trametinib 0.31 37.47 ulixertinib 0.32 2.48
查看英文原文 English abstract
Introduction: We aimed to characterize the preclinical pharmacokinetics (PK) of a series of 20 anticancer agents in highly immunodeficient female NOD scid gamma (NSG) mice to provide clearance and exposure data for agents under investigation by the NCI PDX Development and Trial Centers Research Network (PDXNet).
Methods: The series of 20 anticancer agents (inhibitors of CDK4/6, PI3K-beta/PI3K-delta, ATR, MEK1/2, PI3K, microtubule, EZH2, BCL-2, PARP, histone deacetylase, gamma-secretase, FGFR, SHP2, and ERK1/2, as well as a SMAC mimetic) were administered to female NSG mice via IV, PO, or IP routes to characterize plasma exposures under conditions used for PDX efficacy testing. Serial plasma samples were collected 15, 30, 60, 120, 240, 360, 480, and 1440 minutes after dosing. Drug concentrations were quantified using validated LC-MS/MS assays. PK parameters were calculated using non-compartmental analysis.
Results: The PK for each agent was determined, and the clearance and half-life values are listed in the table below. The PK metrics for Navitoclax could not be calculated. Due to higher metabolic rates, mice show faster PK processes. They generally had shorter half-lives and higher weight-normalized clearance than humans. Copanlisib, Navitoclax, and Trametinib were exceptions.
Conclusion: These PK data are critical for understanding the antitumor activities of agents studied by the PDXNet and will aid investigators in developing new approach methodologies for preclinical safety studies in preparation for human clinical trials.
Pharmacokinetic Analysis Agent Clearance (L/hr*kg) Half-life (Hours) abemaciclib 1.32 10.99 AZD8186 4 2.42 BAY-1895344 1.77 4.72 birinapant 4.19 8.47 cobimetinib 0.76 21.9 copanlisib 9.42 2.78 docetaxel 1.71 1.17 EPZ-011989 1.13 2.06 niraparib 1.25 10.11 olaparib 4.63 3.44 panobinostat 241.55 3.80 RO4929097 1.01 4.2 rogaratinib 0.46 3.86 romidepsin 6.2 14.38 selumetinib 0.77 5.91 SHP099 0.35 55.12 talozoparib 0.295 4.26 trametinib 0.31 37.47 ulixertinib 0.32 2.48
利益披露 Disclosure
M. Chama, None..
R. A. Schoon, None.