小干扰RNA(siRNA)代表了一类新的药物,具有巨大的潜力,可以对抗以前无法用药的疾病。经过近二十年的努力,解决了裸未修饰siRNA的药物谱差的问题,这种新模式终于实现了,有五名特工(patisiran,Givosiran,lumasiran,inclisiran,和vutrisiran)自2018年以来获得批准,许多其他项目处于临床开发的不同阶段。与小分子药物和蛋白质疗法不同,siRNA有不同的大小,不同的作用机制,不同的物理化学和药理特性,和相应的独特的PK/PD关系。为了支持siRNA的持续发展,深入了解siRNA的PK/PD和临床药理学相关特征非常重要。由于目前大多数siRNA产物都是通过N-乙酰半乳糖胺(GalNAc)缀合的,这篇综述的重点是GalNAc缀合的siRNA的PK/PD和临床药理学,包括它们的吸收,分布,新陈代谢,排泄(ADME)特性,PK/PD模型,药物-药物相互作用,特殊人群的临床药理学,和安全性评价。此外,与siRNA作为治疗方式的发展有关的必要背景信息,包括它的作用机制,siRNA的优势,裸siRNA的问题,以及用于增强siRNA临床效用的策略,也被覆盖了。这篇综述的目的是作为siRNAPK/PD的“引物”,我希望读者,特别是那些对siRNA治疗背景有限的人,阅读这篇综述后,将对siRNAPK/PD有一个基本的了解。本文受版权保护。保留所有权利。
Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously \"undruggable\" diseases. After nearly 2 decades of efforts in addressing the problems of the poor drug profile of naked unmodified siRNAs, this new modality has finally come to fruition, with 5 agents (patisiran, givosiran,
lumasiran, inclisiran, and vutrisiran) being approved since 2018, and with many others in the different phases of clinical development. Unlike small-molecule drugs and protein therapeutics, siRNAs have different sizes, distinct mechanisms of action, differing physicochemical and pharmacological properties, and, accordingly, a unique pharmacokinetic/pharmacodynamic (PK/PD) relationship. To support the continuous development of siRNAs, it is important to have a thorough and deep understanding of the PK/PD and clinical pharmacology related features of siRNAs. As most of the current siRNA products are conjugated by N-acetylgalactosamine (GalNAc), this review focuses on the PK/PD relationships and clinical pharmacology of GalNAc-conjugated siRNAs, including their absorption, distribution, metabolism, excretion (ADME) properties, PK/PD models, drug-drug interactions, clinical pharmacology in special populations, and safety evaluation. In addition, necessary background information related to the development of siRNAs as a therapeutic modality, including the mechanisms of action, the advantages of siRNAs, the problems of naked siRNAs, as well as the strategies used to enhance the clinical utility of siRNAs, have also been covered. The goal of this review is to serve as a \"primer\" on siRNA PK/PD, and I hope the readers, especially those who have a limited background on siRNA therapeutics, will have a fundamental understanding of siRNA PK/PD and clinical pharmacology after reading this review.