Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Quantitative Biology SE, Data Sciences and Quantitative Biology, Discovery Sciences, AstraZeneca, Gothenburg, Sweden.
Nucleic Acid Ther. 2022 Dec;32(6):507-512. doi: 10.1089/nat.2022.0010. Epub 2022 Jul 22.
Small interfering RNAs (siRNAs) with -acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal for study design and human dose prediction. However, the literature is sparse on translational data for this modality, and pharmacokinetics in the liver is seldom measured. To overcome these difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in various species and applied the kinetic-pharmacodynamic modeling approach to estimate the biophase (liver) half-life and the potency. Our analysis indicates that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and 1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8 times longer in human than in mouse, and generally 1-3 times longer in human than in monkey. The analysis indicates that the siRNAs are more potent in human than in mouse and monkey.
带有 -N-乙酰半乳糖胺（GalNAc）缀合的小干扰 RNA（siRNA）可提高肝脏摄取率，是一类新兴的治疗肝脏疾病的药物。了解药代动力学和药效学如何转化对于研究设计和人类剂量预测至关重要。然而，关于这种模式的转化数据的文献很少，并且很少测量肝脏中的药代动力学。为了克服这些困难，我们收集了各种物种中 11 种 GalNAc-siRNA 的时间过程生物标志物数据，并应用了动力学-药效学建模方法来估计生物相（肝脏）半衰期和效力。我们的分析表明，在小鼠中，生物相半衰期为 0.6-3 周，在猴子中为 1-8 周，在人类中为 1.5-14 周。对于单个 siRNA，其生物相半衰期在人类中比在小鼠中长 1-8 倍，通常在人类中比在猴子中长 1-3 倍。分析表明，siRNA 在人类中的效力比在小鼠和猴子中更高。
