OliX Pharmaceuticals, Inc., Suwon, South Korea (J.B., B.K.S., Y.Y., M.K., J.C., J.H.P., S.-Y.P., D.-K.L.) and College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, South Korea (J.B., S.H.K.).
OliX Pharmaceuticals, Inc., Suwon, South Korea (J.B., B.K.S., Y.Y., M.K., J.C., J.H.P., S.-Y.P., D.-K.L.) and College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, South Korea (J.B., S.H.K.)
Drug Metab Dispos. 2024 Oct 16;52(11):1262-1270. doi: 10.1124/dmd.124.001805.
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 -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.
在这项研究中，研究了正在开发中的 RNA 干扰治疗药物 OLX702A-075-16 的非临床药代动力学。OLX702A-075-16 是一种新型的 N-乙酰半乳糖胺缀合不对称小干扰 RNA（GalNAc-asiRNA），用于治疗未公开的肝脏疾病。其独特的 16/21 聚体不对称结构降低了非特异性脱靶效应，而不影响疗效。我们在小鼠和大鼠中研究了 OLX702A-075-16 皮下给药后的血浆浓度、组织分布、代谢和肾排泄。用于生物分析的是带有荧光检测的高效液相色谱法。结果表明，OLX702A-075-16 从血浆中快速清除（半衰期为 0.5 至 1.5 小时），主要分布于肝脏和/或肾脏。在其他组织中检测到的 OLX702A-075-16 肝浓度不到 1%。使用带有高分辨率质谱的液相色谱对代谢产物进行了分析，结果表明，完整的双链 OLX702A-075-16 是血浆中的主要化合物。GalNAc 部分主要在肝脏中从有义链代谢，OLX702A-075-16 的未缀合有义链占大鼠肝脏总暴露量的 95%以上。同时，反义链通过外切酶从 3'末端依次丢失核苷酸进行代谢，从大鼠肝脏样品中得到了最多样化的代谢物截断形式。在大鼠中，96 小时内尿液排泄量不到给药剂量的 1%。OLX702A-075-16 的高血浆蛋白结合可能通过肾脏滤过抑制其清除。意义：本研究首次全面描述了 GalNAc-asiRNA 的体内药代动力学。从这项研究中获得的药代动力学见解将有助于了解毒理学和疗效，优化递送平台，并提高临床前物种数据对人类应用的预测能力。
