Details

Autor(en) / Beteiligte

• McDougall, Robin
• Ramsden, Diane
• Agarwal, Sagar
• Agarwal, Saket
• Aluri, Krishna
• Arciprete, Michael
• Brown, Christopher
• Castellanos-Rizaldos, Elena
• Charisse, Klaus
• Chong, Saeho
• Cichocki, Joseph
• Fitzgerald, Kevin
• Goel, Varun
• Gu, Yongli
• Guenther, Dale
• Habtemariam, Bahru
• Jadhav, Vasant
• Janas, Maja
• Jayaraman, Muthusamy
• Kurz, Jeffrey
• Li, Jing
• Liu, Ju
• Liu, Xiumin
• Liou, Steven
• Maclauchlin, Chris
• Maier, Martin
• Manoharan, Muthiah
• Nair, Jayaprakash K
• Robbie, Gabriel
• Schmidt, Karyn
• Smith, Peter
• Theile, Christopher
• Vaishnaw, Akshay
• Waldron, Scott
• Xu, Yuanxin
• Zhang, Xuemei
• Zlatev, Ivan
• Wu, Jing-Tao

Titel

The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of N -Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human

Ist Teil von

• Drug metabolism and disposition, 2022-06, Vol.50 (6), p.781-797

Ort / Verlag

United States

Erscheinungsjahr

2022

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Conjugation of oligonucleotide therapeutics, including small interfering RNAs (siRNAs) or antisense oligonucleotides, to -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, OXLUMO (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio (inclisiran) for the treatment of hypercholesterolemia, the technology has been well validated clinically. Although much knowledge has been gained over decades of development, there is a paucity of published literature on the drug metabolism and pharmacokinetic properties of GalNAc-siRNA. With this in mind, the goals of this minireview are to provide an aggregate analysis of these nonclinical absorption, distribution, metabolism, and excretion (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 asialoglycoprotein receptor-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 in hepatocytes, are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the 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, are 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 pharmacokinetic/pharmacodynamic 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.