A journey into siRNA therapeutics development: A focus on Pharmacokinetics and Pharmacodynamics

siRNA therapeutics are emerging novel modalities targeting highly specific mRNA via RNA interference mechanism. Its unique pharmacokinetics (PKs) and pharmacodynamics (PDs) are significant challenges for clinical use. Furthermore, naked siRNA is a highly soluble macromolecule with a negative charge, making plasma membrane penetration a significant hurdle. It is also vulnerable to nuclease degradation. Therefore, advanced formulation technologies, such as lipid nanoparticles and N-acetylgalactosamine conjugation, have been developed and are now used in clinical practice to enhance target organ delivery and stability. The innate complex biological mechanisms of siRNA, along with its formulation, are major determinants of the PK/PD characteristics of siRNA products. To systematically and quantitatively understand these characteristics, it is essential to develop and utilize quantitative PK/PD models for siRNA therapeutics. In this review, the effects of formulation on the PKs and PK/PD models of approved siRNA products were presented, highlighting the importance of selecting appropriate biomarkers and understanding formulation, PKs, and PDs for quantitative interpreting the relationship between plasma concentration, organ concentration, biomarkers, and efficacy.