Background/Objectives: N-acetyl-galactosamine small interfering RNAs (GalNAc-siRNA) are an emerging class of drugs due to their durable knockdown of disease-related proteins. Direct conjugation of GalNAc onto the siRNA enables targeted uptake into hepatocytes via GalNAc recognition of the Asialoglycoprotein Receptor (ASGPR). With a transient plasma exposure combined with a prolonged liver half-life, GalNAc-siRNA exhibits distinct disposition characteristics. We aimed to develop a generic GalNAc-siRNAs whole-body physiologically based pharmacokinetic-pharmacodynamic (WB-PBPK-PD) model for describing the pharmacokinetic-pharmacodynamic (PK-PD) relationship and overall tissue distribution in the open-source platform Open Systems Pharmacology Suite.

Methods: Model development was performed using published studies in mice leveraging the PK-Sim (R) standard implementation for large molecules with added implementations of ASGPR-mediated liver disposition and downstream target effects. Adequate model performance was achieved across study measurements and included studies adopting a combination of global and compound-specific parameters.

Results: The analysis identified significant compound dependencies, e.g., endosomal stability, with direct consequences for the pharmacological effect. Additionally, knowledge gaps in mechanistic understanding related to extravasation and overall tissue distribution were identified during model development. The presented study provides a generic WB-PBPK-PD model for the investigation of GalNAc-siRNAs implemented in a standardized open-source platform.