Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
Nucleic Acid Ther. 2021 Aug;31(4):298-308. doi: 10.1089/nat.2020.0911. Epub 2021 Apr 23.
It is well documented and generally accepted that human clearance (CL) of unconjugated single-strand antisense oligonucleotides (ASOs) can be directly predicted from monkeys by body weight (BW) on a mg/kg dose basis. However, the scaling for triantennary -acetyl galactosamine (GalNAc)-conjugated ASOs has not been fully established. In this study, we retrospectively analyzed pharmacokinetic data from 9 GalNAc-conjugated and 12 unconjugated single-stranded ASOs (ten 2'-methoxyethyl and two 2', 4'-constrained ethyl ASOs) to identify an appropriate allometric scaling factor between the two species. In addition, we compared the trough plasma concentrations ( a surrogate for tissue exposure) between monkeys and humans at comparable dose levels, aiming at predicting tissue distribution in humans from monkeys. Overall, the median plasma CL ratios (monkey CL/human CL) were 1.05 and 0.94 when CL was normalized by BW, as compared with 0.33 and 0.29 when CL was normalized by body surface area (BSA) for the 12 unconjugated and 9 GalNAc-conjugated ASOs, respectively. Similarly, the median ratios ( in monkeys/ in humans) were 0.96 and 1.71, respectively, when was normalized by mg/kg dose as compared with 3.10 and 5.50 when was normalized by mg/m dose for the same unconjugated and conjugated ASOs, respectively. Equivalent CL and dose-normalized plasma between monkeys and humans suggest similar pharmacokinetic profiles and tissue distribution between the two species on a per kilogram BW basis. In conclusion, human CL and plasma (a surrogate of tissue distribution) can be directly predicted (1:1 or within twofold) from monkeys by BW on a mg/kg dose basis but these parameters can be under- or over-predicted by BSA on a mg/m dose basis. These results provide evidence for single species scaling from monkeys to humans directly and, thus, they can facilitate early human dose prediction in ASO drug development.
文献中已有充分记载并得到广泛认可，即未缀合单链反义寡核苷酸（ASO）的人体清除率（CL）可通过以毫克/千克剂量为单位的体质量（BW）直接从猴子推算出来。然而，三触角乙酰半乳糖胺（GalNAc）缀合 ASO 的缩放比例尚未完全确定。在这项研究中，我们回顾性分析了 9 种 GalNAc 缀合和 12 种未缀合单链 ASO（10 种 2'-甲氧基乙基和 2 种 2'，4'-约束乙基 ASO）的药代动力学数据，以确定两种物种之间的适当比例缩放因子。此外，我们还比较了猴子和人类在可比剂量水平下的谷底血浆浓度（组织暴露的替代物），旨在从猴子推算出人体的组织分布。总体而言，当 CL 按 BW 归一化时，猴子 CL/人 CL 的中位数比值分别为 1.05 和 0.94，而当 CL 按体表面积（BSA）归一化时，12 种未缀合和 9 种 GalNAc 缀合 ASO 的比值分别为 0.33 和 0.29。同样，当 按 mg/kg 剂量归一化时，猴子中/人体中的比值分别为 0.96 和 1.71，而当 按 mg/m 剂量归一化时，同一未缀合和缀合 ASO 的比值分别为 3.10 和 5.50。猴子和人类的 CL 和剂量归一化的血浆 相当，表明在每公斤 BW 基础上，两种物种的药代动力学特征和组织分布相似。总之，以毫克/千克剂量为单位，按 BW 直接从猴子推算出人 CL 和血浆（组织分布的替代物）（1:1 或两倍以内），但以毫克/平方米剂量为单位，BSA 可能会导致低估或高估这些参数。这些结果为直接从猴子到人类的单物种缩放提供了证据，从而可以促进 ASO 药物开发中早期的人体剂量预测。
