Multiphysics-Informed Pharmacokinetic Modeling of Systemic Exposure of Intramuscularly Injected LNPs.

Abstract

Lipid nanoparticle (LNP) constructs have been widely developed for gene therapy delivery. Understanding local absorption and presystemic clearance kinetics of LNPs, however, remains limited. This subsequently restrains the prediction and assessment of the systemic exposure of locally injected LNPs. As such, a multiscale computational approach was developed by integrating multiphysics simulation of intramuscular absorption kinetics of LNPs with whole-body pharmacokinetics modeling, bridged by a presystemic lymphatic kinetic model. The overall framework was enabled by utilizing physiological parameters obtained from the literature and drug-related parameters derived from experiments. The multiscale modeling and simulation approach predicted the systemic exposure of LNPs administered intramuscularly, with a high degree of agreement between the predicted and the experimental data. Sensitivity analyses revealed that the local absorption rate, pinocytosis presystemic clearance rate, and lymph flow rate of the presystemic lymphatic compartment had the most significant impacts on Cmax. The study yielded refreshing perspectives on estimating systemic exposures of locally injected LNPs and their safety and effectiveness.