PT  - JOURNAL ARTICLE
AU  - Saeho Chong
AU  - Sagar Agarwal
AU  - Saket Agarwal
AU  - Krishna C. Aluri
AU  - Michael Arciprete
AU  - Christopher Brown
AU  - Klaus Charisse
AU  - Joseph Cichocki
AU  - Kevin Fitzgerald
AU  - Varun Goel
AU  - Yongli Gu
AU  - Dale Guenther
AU  - Bahru Habtemariam
AU  - Vasant Jadhav
AU  - Maja Janas
AU  - Muthusamy Jayaraman
AU  - Jeff Kurz
AU  - Jing Li
AU  - Steven Liou
AU  - Ju Liu
AU  - Xiumin Liu
AU  - Christopher Maclauchlin
AU  - Martin Maier
AU  - Muthiah Manoharan
AU  - Robin McDougall
AU  - Jay Nair
AU  - Diane Ramsden
AU  - Gabriel Robbie
AU  - Karyn Schmidt
AU  - Peter Smith
AU  - Christopher Theile
AU  - Akshay Vaishnaw
AU  - Scott Waldron
AU  - Jing-Tao Wu
AU  - Yuanxin Xu
AU  - Xuemei Zhang
AU  - Ivan Zlatev
AU  - Elena castellanos-Rizaldos
TI  - The Nonclinical Disposition and PK/PD Properties of GalNAc-conjugated siRNA Are Highly Predictable and Build Confidence in Translation to Man
AID  - 10.1124/dmd.121.000428
DP  - 2021 Jan 01
TA  - Drug Metabolism and Disposition
PG  - DMD-MR-2021-000428
4099  - http://dmd.aspetjournals.org/content/early/2021/06/18/dmd.121.000428.short
4100  - http://dmd.aspetjournals.org/content/early/2021/06/18/dmd.121.000428.full
AB  - Conjugation of oligonucleotide therapeutics, including small interfering ribonucleic acids (siRNAs) or antisense oligonucleotides (ASOs) to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI® (givosiran) for the treatment of acute hepatic porphyria, OXLUMOTM (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio® (inclisiran) for the treatment of hypercholesterolemia, the technology has been well-validated clinically. While much knowledge has been gained over decades of development there is a paucity of published literature on the DMPK properties of GalNAc-siRNA. With this in mind the goals of this mini-review are to provide an aggregate analysis of these nonclinical ADME data to build confidence on the translation of these properties to human. Upon subcutaneous administration, GalNAc-conjugated siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic (PK) properties that reflect rapid elimination through ASGPR-mediated uptake from circulation into hepatocytes. These studies confirm that liver PK, including half-life and, most importantly, siRNA levels in RNA-induced silencing complex (RISC) in hepatocytes are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the absorption, distribution, metabolism and excretion (ADME) properties of GalNAc-conjugated siRNAs. These studies demonstrate that the PK/PD and ADME properties of GalNAc-conjugated siRNAs are highly conserved across species, largely predictable, and can be accurately scaled to human, allowing us to identify efficacious and safe clinical dosing regimens in the absence of human liver PK profiles. Significance Statement Several nonclinical ADME studies have been conducted in order to provide a comprehensive overview of the disposition and elimination of GalNAc-conjugated siRNAs and the PK/PD translation between species. These studies demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species building confidence in the ability to extrapolate to human.