Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling
文献类型：期刊论文
| 作者 | He, Yifei2,3; Zhu, Chenggu1; Lei, Peng3; Yang, Chen3; Zhang, Yifan3 ; Zheng, Yuandong3; Diao, Xingxing2,3
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| 刊名 | JOURNAL OF PHARMACEUTICAL ANALYSIS
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| 出版日期 | 2025-05-01 |
| 卷号 | 15期号:5页码:15 |
| 关键词 | PROTAC Vepdegestrant (ARV-471) Radiolabeling In vitro-in vivo extrapolation (IVIVE) Physiologically based pharmacokinetic (PBPK) model |
| ISSN号 | 2095-1779 |
| DOI | 10.1016/j.jpha.2024.101175 |
| 通讯作者 | Zheng, Yuandong(ydzheng@simm.ac.cn) ; Diao, Xingxing(xxdiao@simm.ac.cn) |
| 英文摘要 | Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, 14C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of Xi'an Jiaotong University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| WOS关键词 | IN-VIVO EXTRAPOLATION ; PHYSIOLOGICALLY-BASED PHARMACOKINETICS ; TARGETING CHIMERAS PROTACS ; METABOLIC-CLEARANCE ; VITRO ; PERMEABILITY ; DISSOLUTION ; ABSORPTION ; PARAMETERS ; STRATEGY |
| 资助项目 | National Natural Science Foundation of China[82373938] ; National Natural Science Foundation of China[82104275] ; National Natural Science Foundation of China[82204585] ; Key Technologies R&D Program of Guangdong Province, China[2023B1111030004] ; National Key R&D Program of China[2022YFF120260 0] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001499764500003 |
| 出版者 | ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318180]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zheng, Yuandong; Diao, Xingxing |
| 作者单位 | 1.Wuxi Beita Pharmatech Co Ltd, Wuxi 214437, Jiangsu, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | He, Yifei,Zhu, Chenggu,Lei, Peng,et al. Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling[J]. JOURNAL OF PHARMACEUTICAL ANALYSIS,2025,15(5):15. |
| APA | He, Yifei.,Zhu, Chenggu.,Lei, Peng.,Yang, Chen.,Zhang, Yifan.,...&Diao, Xingxing.(2025).Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling.JOURNAL OF PHARMACEUTICAL ANALYSIS,15(5),15. |
| MLA | He, Yifei,et al."Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling".JOURNAL OF PHARMACEUTICAL ANALYSIS 15.5(2025):15. |
入库方式： OAI收割
来源：上海药物研究所
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