Whole-Body Physiologically Based Pharmacokinetic–Pharmacodynamic Modeling for Interspecies Translation and Mechanistic Characterization of Plasma and Tissue Disposition of GalNAc-siRNAs

<b>Introduction/aim:</b> N-acetylgalactoseamine-conjugated small interfering RNAs (GalNAc-siRNAs) are an emerging class of drugs possessing an extensive clinical potential because of their high target specificity to the asialoglycoprotein receptor (ASGPR) in hepatocytes. Overall, GalNAc-sRNAs are well-tolerated across species but differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties have been observed. Furthermore, despite GalNAc-siRNA's high liver specificity, distribution into off-target organs does occur. Through whole-body physiologically based pharmacokinetic (PBPK) modeling, this study seeks to mechanistically address species differences, establish clinical PK-PD relationships, and characterize off-target organ accumulation, ultimately expediting the preclinical-to-clinical translation of GalNAc-sRNAs in drug development. <b>Materials/Methods:</b> For model development, validation, and establishment of species' translations, three in-house GalNAc-siRNAs with PK data from different biospecimens, as well as downstream effects on mRNA and target proteins in mouse, monkey, and human, were leveraged. A WB-PBPK-PD legacy model, developed as an extension to the generic model for large molecules in the platform Open Systems Pharmacology Suite, was further validated and applied to address the specific aims of this study. <b>Results:</b> The model successfully quantified the PK-PD relationships across species and characterized accumulation in off-target organs. The model further sheds light on species-specific differences, such as liver permeability, subcutaneous absorption rate, as well as PD-related mechanisms. Moreover, the model confirmed previously established compound-specific pharmacokinetic differences and similarities. <b>Conclusions</b>: This PBPK-PD can serve as a framework for future investigations of novel GalNAc-siRNAs across species.