Tian Zhiteng, Luo Hui, Chu Yantao, Liu Yanhong, Gao Shan, Song Ling, Yang Zhenzhen, Liu Dongyang
Drug Clinical Trial Center, Peking University Third Hospital, Beijing, 100191, China.
Suzhou Ribo Life Science Co. Ltd., Jiangsu, 215300, China.
Clin Pharmacokinet. 2025 May 3. doi: 10.1007/s40262-025-01513-4.
The emerging N-acetylgalactosamine-small interfering RNA (GalNAc-siRNA) conjugates lead the way for liver-targeting delivery to exert gene-silencing therapeutic effects. To facilitate the drug development of GalNAc-siRNA, further detailed understanding of the key modality-specific mechanisms underlying the temporal discordance between pharmacokinetics and pharmacodynamics and how these processes can be extrapolated from animals to humans is needed.
A mechanistic minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK-PD) model for an investigational new apolipoprotein C-III (APOC3)-silencing GalNAc-siRNA (RBD5044) was developed using available pharmacokinetic/pharmacodynamic (PK/PD) data. The aim was to explore hepatic-targeting delivery processes, the PK/PD relationship, and interspecies translation.
First, multiple PK/PD datasets from mice were satisfactorily fitted using the mPBPK-PD model. Second, we translated the mice model to the monkey model, validated it, and then extrapolated from mice and monkeys to humans to simulate the PK/PD characteristics. We then mechanistically summarized and proposed the essential in vivo delivery processes of GalNAc-siRNA after subcutaneous administration (termed "ADUEB": Absorption [into system circulation], Disposition [distribution to liver target and elimination], Uptake [into hepatocytes], Escape [from endosome and lysosome compartments], and Binding [with argonaute2 to form RNA-induced silencing complex]). The targeting delivery coefficients of these processes achieved with the model using RBD5044 and the published data of another GalNAc-siRNA (fitusiran) quantitatively reflected the delivery efficiency and rate-limiting factors in targeted hepatocytes.
This study successfully constructed the mPBPK-PD model and conducted interspecies extrapolation for a GalNAc-siRNA targeting APOC3. Promising quantitative insights into a hepatic-targeted GalNAc-siRNA delivery system are provided to characterize the unique temporal disconnection of PK/PD properties and evaluate the key in vivo delivery processes. It will promote model-informed strategies and quantitative mechanistic understanding to support efficient drug development, evaluation, and clinical application of this modality in the future.
新兴的N - 乙酰半乳糖胺 - 小干扰RNA（GalNAc - siRNA）偶联物引领了肝脏靶向递送以发挥基因沉默治疗效果的道路。为促进GalNAc - siRNA的药物开发，需要进一步详细了解药代动力学和药效学之间时间不一致背后的关键模式特异性机制，以及这些过程如何从动物外推至人类。
利用可用的药代动力学/药效学（PK/PD）数据，开发了一种用于研究新型载脂蛋白C - III（APOC3）沉默GalNAc - siRNA（RBD5044）的基于最小生理药代动力学/药效学（mPBPK - PD）的机制模型。目的是探索肝脏靶向递送过程、PK/PD关系及种间外推。
首先，使用mPBPK - PD模型令人满意地拟合了来自小鼠的多个PK/PD数据集。其次，我们将小鼠模型转化为猴模型，进行了验证，然后从小鼠和猴外推至人类以模拟PK/PD特征。然后，我们从机制上总结并提出了皮下给药后GalNAc - siRNA在体内的基本递送过程（称为“ADUEB”：吸收[进入体循环]、处置[分布至肝脏靶标并消除]、摄取[进入肝细胞]、逃逸[从内体和溶酶体区室]以及结合[与AGO2形成RNA诱导沉默复合体]）。使用RBD5044通过该模型获得的这些过程的靶向递送系数以及另一种GalNAc - siRNA（fitusiran）的已发表数据定量反映了靶向肝细胞中的递送效率和限速因素。
本研究成功构建了针对靶向APOC3的GalNAc - siRNA的mPBPK - PD模型并进行了种间外推。为肝脏靶向GalNAc - siRNA递送系统提供了有前景的定量见解，以表征PK/PD特性独特的时间脱节并评估关键的体内递送过程。它将促进基于模型的策略和定量机制理解，以支持该模式在未来的高效药物开发、评估和临床应用。
