PT  - JOURNAL ARTICLE
AU  - Ban, Jihye
AU  - Seo, Bong Kyo
AU  - Yu, Yunmi
AU  - Kim, Minkyeong
AU  - Choe, Jeongyong
AU  - Park, June Hyun
AU  - Park, Shin-Young
AU  - Lee, Dong-Ki
AU  - Kim, So Hee
TI  - Nonclinical Pharmacokinetics Study of OLX702A-075-16, <em>N</em>-Acetylgalactosamine Conjugated Asymmetric Small Interfering RNA (GalNAc-asiRNA)
AID  - 10.1124/dmd.124.001805
DP  - 2024 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1262--1270
VI  - 52
IP  - 11
4099  - http://dmd.aspetjournals.org/content/52/11/1262.short
4100  - http://dmd.aspetjournals.org/content/52/11/1262.full
SO  - Drug Metab Dispos2024 Nov 01; 52
AB  - In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference therapeutic currently in development, were investigated. OLX702A-075-16 is a novel N-acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy. We investigated the plasma concentration, tissue distribution, metabolism, and renal excretion of OLX702A-075-16 following a subcutaneous administration in mice and rats. For bioanalysis, high-performance liquid chromatography with fluorescence detection was used. The results showed rapid clearance from plasma (0.5 to 1.5 hours of half-life) and predominant distribution to the liver and/or kidney. Less than 1% of the liver concentration of OLX702A-075-16 was detected in the other tissues. Metabolite profiling using liquid chromatography coupled with high-resolution mass spectrometry revealed that the intact duplex OLX702A-075-16 was the major compound in plasma. The GalNAc moiety was predominantly metabolized from the sense strand in the liver, with the unconjugated sense strand of OLX702A-075-16 accounting for more than 95% of the total exposure in the rat liver. Meanwhile, the antisense strand was metabolized by the sequential loss of nucleotides from the 3′-terminus by exonuclease, with the rat liver samples yielding the most diverse truncated forms of metabolites. Urinary excretion over 96 hours was less than 1% of the administered dose in rats. High plasma protein binding of OLX702A-075-16 likely inhibited its clearance through renal filtration.SIGNIFICANCE STATEMENT This study presents the first comprehensive characterization of the in vivo pharmacokinetics of GalNAc-asiRNA. The pharmacokinetic insights gained from this research will aid in understanding toxicology and efficacy, optimizing delivery platforms, and improving the predictive power of preclinical species data for human applications.