Cross-Species Translation of Biophase Half-Life and Potency of GalNAc-Conjugated SiRNAs

Overview

Journal Nucleic Acid Ther

Specialties Biochemistry
Molecular Biology
Pharmacology

Date 2022 Jul 22

PMID 35867041

Authors

Alessandro Boianelli

Yasunori Aoki

Maxim Ivanov

Anders Dahlen

Peter Gennemark

Affiliations

Soon will be listed here.

Abstract

Small interfering RNAs (siRNAs) with -acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal for study design and human dose prediction. However, the literature is sparse on translational data for this modality, and pharmacokinetics in the liver is seldom measured. To overcome these difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in various species and applied the kinetic-pharmacodynamic modeling approach to estimate the biophase (liver) half-life and the potency. Our analysis indicates that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and 1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8 times longer in human than in mouse, and generally 1-3 times longer in human than in monkey. The analysis indicates that the siRNAs are more potent in human than in mouse and monkey.

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