Developing physiologically based PK (PBPK) models to facilitate LNP based mRNA therapeutics development

We describe construction of a whole-body physiologically based pharmacokinetic (PBPK) model of LNP (lipid nanoparticle) based mRNA therapeutics using biodistribution data in rodents. At the tissue level, the model includes mRNA cellular uptake, mRNA escape, and the translation of the encoded protein. The calibrated model is then used to determine factors modulating systemic and liver mRNA PK and the dynamics of protein expression in the liver. We demonstrate the utility of the model in projecting human clinical PK using appropriate allometric scaling of physiological and mRNA dependent parameters. The PBPK model is then expanded to the case of secreted proteins using the two-pore model formalism. Scaling of the model to human demonstrates reasonable agreement with available clinical protein PK data. Exploration of mechanistic parameters identifies mRNA design features critical for optimizing protein dynamics for both intracellular and secreted proteins. The PBPK model serves as a general platform to strengthen our understanding of the ADME properties of LNP based mRNA therapeutics and support preclinical to clinical translation.