RT Journal Article
SR Electronic
T1 The Nonclinical Disposition and PK/PD Properties of GalNAc-conjugated siRNA Are Highly Predictable and Build Confidence in Translation to Man
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-MR-2021-000428
DO 10.1124/dmd.121.000428
A1 Chong, Saeho
A1 Agarwal, Sagar
A1 Agarwal, Saket
A1 Aluri, Krishna C.
A1 Arciprete, Michael
A1 Brown, Christopher
A1 Charisse, Klaus
A1 Cichocki, Joseph
A1 Fitzgerald, Kevin
A1 Goel, Varun
A1 Gu, Yongli
A1 Guenther, Dale
A1 Habtemariam, Bahru
A1 Jadhav, Vasant
A1 Janas, Maja
A1 Jayaraman, Muthusamy
A1 Kurz, Jeff
A1 Li, Jing
A1 Liou, Steven
A1 Liu, Ju
A1 Liu, Xiumin
A1 Maclauchlin, Christopher
A1 Maier, Martin
A1 Manoharan, Muthiah
A1 McDougall, Robin
A1 Nair, Jay
A1 Ramsden, Diane
A1 Robbie, Gabriel
A1 Schmidt, Karyn
A1 Smith, Peter
A1 Theile, Christopher
A1 Vaishnaw, Akshay
A1 Waldron, Scott
A1 Wu, Jing-Tao
A1 Xu, Yuanxin
A1 Zhang, Xuemei
A1 Zlatev, Ivan
A1 castellanos-Rizaldos, Elena
YR 2021
UL http://dmd.aspetjournals.org/content/early/2021/06/18/dmd.121.000428.abstract
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.