Abstract
Introduction
N-Acetyl-galactosamine small interfering RNAs (GalNAc-siRNA) is an emerging class of drugs due to their durable knockdown of disease related proteins. Conjugation onto GalNAc allows for target specific uptake into hepatocytes via the Asia Glycoprotein Receptor (ASGPR). With a transient plasma exposure combined with a rapid liver uptake and prolonged half-life in the liver, GalNAc-siRNA exhibits distinct disposition characteristics. Therefore, we aimed to develop a generic GalNAc-siRNAs Whole-Body Physiological-Based Pharmacokinetic-Pharmacodynamic (WB-PBPK-PD) model for the means of describing the pharmacokinetic-pharmacodynamic (PK-PD) relationship and overall tissue distribution.
Methods
For model development a reference data set was compiled from published studies on GalNAc-siRNAs with different stabilization chemistry and different target proteins in mice. The WB-PBPK model structure leveraged the PK-Sim default implementation for large molecules, e.g., including the two-pore-formalism, included in the open-source platform Open System Pharmacology Suite. Specification of intracellular dynamics and efficacy was further implemented to describe mRNA and downstream protein expression of target protein.
Results
Overall, the generic implementation described the observed data within a 2-fold difference across all studies adopting a mix of global and compound specific parameters. The analysis identified significant compound variabilities, e.g., endosomal stability, with direct consequences for the pharmacological effect. Additionally, the model identified knowledge gaps in mechanistic understanding related to extravasation and overall tissue distribution.
Conclusion
The presented study provides a generic WB-PBPK-PD model for the investigation of GalNAc-siRNAs implemented in an open-source platform.