(T-086) Development of a Whole-Body Physiologically Based Pharmacokinetics (PBPK) Model for Predicting Dynamics of mRNA and Protein for LNP-Encapsulated mRNA Therapeutics

Lei Ci, n/a – Associate Scientific Director, Clinical Pharmacology, Pharmacometrics & Clinical Pharmacology, Moderna, Inc; Linh Van, n/a – Director, Pharmacometrics & Clinical Pharmacology, Translational Medicine, Moderna, Inc; Hojjat Bazzazi, n/a – Director, Quantitative Systems Pharmacology, Pharmacometrics & Clinical Pharmacology, Moderna, Inc

Objectives: Development of a platform whole-body physiologically based pharmacokinetic (PBPK) model for lipid nanoparticle (LNP)-mRNA based therapeutics. The PBPK model captures the mechanism of action of the protein production for enzyme replacement therapy.

Methods: A whole-body PBPK model was developed to include LNP transport, cellular uptake, and protein translation through mRNA in various organ tissues. The model was calibrated to mRNA and protein kinetic bio-distribution data across different tissues in rat [1]. A Hill function was used to model transport of LNP across the endothelial layer into the tissue space. Local and global sensitivity analysis were conducted to identify key determinants of protein expression in the liver. Exploratory simulations were performed by varying key parameters to investigate changes in protein expression under different scenarios. Model was successfully scaled to human to investigate parameters impacting mRNA pharmacokinetics.

Results: The calibrated model accurately describes the kinetics of mRNA and protein expression in plasma and various tissue types. Initial data exploration showed that at a given time majority of the injected mRNA (~70%) is in liver, plasma, and the muscle. Over 90% of the expressed protein is in the liver; likely because the liver is the key site of LNP-mRNA disposition and mRNA to protein translation. Local and global sensitivity analysis demonstrated that protein exposure in the liver is highly dependent on translation and escape rates. The mRNA exposure in the liver is critically dependent on LNP-mRNA dependent parameters: mRNA and LNP degradation rates, uptake rates, and LNP influx rates into the tissue from the vasculature. The EC50 of the Hill function for LNP influx rate critically influenced protein AUC in the liver in a highly nonlinear manner. Allometric scaling of uptake and tissue influx rates accurately predicted mRNA PK in human from rat [2].

Conclusions: Whole-body PBPK model was developed and calibrated to mRNA and protein data in rat. Detailed sensitivity analysis was performed to identify significant parameters impacting protein and mRNA exposure in liver tissue. The model was successfully scaled to human. The whole-body PBPK model significantly improves our mechanistic understanding of factors influencing mRNA and protein dynamics in target tissues. This model may also serve as an effective tool for projecting human mRNA dynamics from preclinical species.

Citations: [1] Ci, Lei et al. “Biodistribution of Lipid 5, mRNA, and Its Translated Protein Following Intravenous Administration of mRNA-Encapsulated Lipid Nanoparticles in Rats.” Drug metabolism and disposition: the biological fate of chemicals vol. 51,7 (2023): 813-823.
[2] August, Allison et al. “A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus.” Nature medicine vol. 27,12 (2021): 2224-2233.