Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling.

Journal of pharmaceutical analysis Pub Date : 2025-05-01 Epub Date: 2024-12-28 DOI:10.1016/j.jpha.2024.101175
Yifei He, Chenggu Zhu, Peng Lei, Chen Yang, Yifan Zhang, Yuandong Zheng, Xingxing Diao
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Abstract

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.

利用PBPK模型对ARV-471临床前无线电ADME特性进行预测。
靶向蛋白水解嵌合体(Proteolysis-targeting chimeras, PROTACs)是一类很有前途的药物,它比传统的小分子抑制剂更有效地靶向致病蛋白,有可能彻底改变药物发现和治疗策略。然而,体外和体内数据之间的联系知之甚少,阻碍了对PROTACs的吸收、分布、代谢和排泄(ADME)的全面了解。本研究以目前处于乳腺癌三期临床试验的14c标记vepdegestrant (ARV-471)为模型,通过建立基于生理的药代动力学(PBPK)模型,表征其临床前ADME特性,并模拟其临床药代动力学(PK)。对于体外外推法(IVIVE),肝细胞清除率与体内大鼠PK数据的相关性比肝微粒体清除率更密切。最初在大鼠身上开发并验证的PBPK模型,准确模拟了ARV-471在喂养和禁食状态下的PK,参数与观测值相差不超过1.75倍。根据体外ADME数据,人体模型密切反映了30mg时的产后剂量血浆谱。此外,没有在体外鉴定出人类特异性代谢物,并且大鼠的代谢谱可能与人类的代谢谱重叠。这项工作通过阐明体外和体内特性之间的相关性,为开发未来的PROTAC药物提供了路线图。
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