Physiologically based pharmacokinetic (PBPK) models facilitate the mechanistic study of drug delivery. We developed a PBPK-quantitative systems pharmacology (QSP) model to study lipid nanoparticle (LNP)-mRNA therapeutics in Crigler-Najjar syndrome. Sensitivity analyses revealed that mRNA stability, translation, and cellular uptake rate significantly influence protein expression, while liver influx rate of LNPs does not. Modulating mRNA degradation can tune protein levels unless the protein's half-life is very short. LNP degradation and mRNA escape from endosomes are crucial for protein expression, with a linear relationship observed. Including LNP recycling, simulations show a second mRNA peak dependent on recycling and re-uptake rates. The model aids in optimizing dosing schedules and designing effective mRNA therapeutics.
Learning Objectives:
To discuss the potential of quantitative model to integrate preclinical PK, PD and tissue biodistribution data to project mRNA and protein exposures.
Summarize different Quantitative Pharmacology approaches to support development of LNP-mRNA therapeutics
Clinical Pharmacology considerations for different disease areas with LNP-mRNAs (vaccines, rare disease)
