Physiologically Based Pharmacokientics Modeling of RNA-LNP to Characterize Clinical Consequence

RNA-based medicines are an emerging therapeutic modality, with several approved siRNA drugs, along with the global deployment of mRNA-based vaccines for COVID-19. There is great interest in the use of mRNA-based drugs as therapeutics, permitting transient expression of a transgene product in vivo. Successful clinical translation of any therapeutic requires understanding of the PK-PD relationship in both preclinical species and in humans. Delivery of mRNA by lipid nanoparticles (LNP) is associated with significant spatiotemporal disconnects in PK and PD, with LNP being rapidly eliminated from the circulation, while transgene product expression persists for hours to days. In this presentation, progress in development of a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for untargeted and targeted mRNA-LNP will be described. There will be a focus on mechanisms of distribution, the impact of LNP targeting on delivery and expression, and engineerable features that can impact transgene expression magnitude and duration.