ArticleDrug design, development and therapy2026
Cross-Species Translation and Target-Dependent Pharmacology of GalNAc-siRNAs Using a Multi-Parameter K-PD Framework for Biophase Kinetics, Apparent Potency, and Pharmacodynamic Turnover.
Article in Drug design, development and therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Small interfering RNAs (siRNAs) conjugated with N-acetylgalactosamine (GalNAc) are liver-targeted therapeutics with sustained activity. However, their cross-species pharmacokinetic (PK) and pharmacodynamic (PD) translation remains poorly defined, particularly regarding target dependence and PD endpoint selection. This study aimed to develop a kinetic-pharmacodynamic (K-PD) modeling framework to characterize their long-term pharmacology, cross-species translational relationships, and target mRNA effects by quantifying biophase half-life, in vivo potency (IDK Methods: Publicly available PD time-course data for 30 GalNAc-siRNAs across four species (mice, rats, monkeys, and humans) were compiled through a targeted search of the literature and other public sources. A unified K-PD modeling framework was applied to estimate key parameters and evaluate cross-species translational behavior and target-related variability. Results: Human biophase half-life exceeded that in preclinical species, whereas human IDK Conclusion: The K-PD modeling framework characterized the cross-species pharmacology of GalNAc-siRNAs, confirmed consistent translational patterns, and identified target-specific effects on PD kinetics. These findings facilitate early human pharmacological prediction, enabling a shift from empirical scaling toward model-informed translational decision-making.
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