Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs.

Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously undruggable diseases. After nearly two 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 five agents (patisiran, givosiran, lumasiran, inclisiran, and vutrisiran) being approved since 2018 and many others in the different phases of clinical development. Unlike small-molecule drugs and protein therapeutics, siRNAs have different sizes, distinct mechanism of action, different physicochemical and pharmacological properties, and accordingly a unique PK/PD relationship. To support the continuous development of siRNA, it is important to have a thorough and deep understanding of the PK/PD and clinical pharmacology related features of siRNAs. Since most of the current siRNA products are conjugated by N-acetylgalactosamine (GalNAc), this review focuses on the PK/PD 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 siRNA as a therapeutic modality, including its mechanism of action, the advantages of siRNAs, the problems of naked siRNAs, as well as the strategies used to enhance the clinical utility of siRNA, 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 limited background on siRNA therapeutics, will have a fundamental understanding on siRNA PK/PD after reading this review. This article is protected by copyright. All rights reserved.