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

ABSTRACT: Introduction/aim: 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-

SUBMITTER: Salim EL 

PROVIDER: S-EPMC12472881 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature