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 N-acetyl galactosamine (GalNAc₃)-conjugated ASOs has not been fully established. In this study, we retrospectively analyzed pharmacokinetic data from 9 GalNAc₃-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 (C_trough, 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 GalNAc₃-conjugated ASOs, respectively. Similarly, the median C_trough ratios (C_trough in monkeys/C_trough in humans) were 0.96 and 1.71, respectively, when C_trough was normalized by mg/kg dose as compared with 3.10 and 5.50 when C_trough was normalized by mg/m² dose for the same unconjugated and conjugated ASOs, respectively. Equivalent CL and dose-normalized plasma C_trough 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 C_trough (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/m² 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.

中文翻译：

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反义寡核苷酸的人类清除和血浆槽暴露的种间缩放：GalNAc3-缀合和未缀合的反义寡核苷酸的回顾性分析

有据可查并普遍接受的是，未缀合的单链反义寡核苷酸 (ASO) 的人体清除率 (CL) 可以直接从猴子的体重 (BW) 以 mg/kg 剂量为基础预测。然而，三触角N-乙酰半乳糖胺 (GalNAc ₃ ) 缀合的 ASO 的缩放比例尚未完全确定。在本研究中，我们回顾性分析了来自 9 个 GalNAc ₃共轭和 12 个未共轭单链 ASO（10 个 2'-甲氧基乙基和两个 2', 4'-约束乙基 ASO）的药代动力学数据，以确定两者之间的适当异速生长比例因子物种。此外，我们比较了谷血浆浓度（C_谷，以相似的剂量水平在猴子和人类之间进行组织暴露的替代物，旨在预测猴子在人类中的组织分布。总体而言，当 CL 通过 BW 归一化时，血浆 CL 比值（猴子 CL/人 CL）的中值分别为 1.05 和 0.94，而当 CL 通过体表面积（BSA）归一化时，12 个未结合和 9 个 GalNAc ₃ -共轭ASO，分别。类似地，当C_谷通过 mg/kg 剂量归一化时，中位C_谷比率（猴子中的 C 谷/人类_中的C_谷）分别为 0.96 和 1.71，而C_{谷时为 3.10 和 5.50}对于相同的未缀合和缀合的 ASO，分别通过 mg/m ^{2剂量标准化。}猴子和人类之间等效的 CL 和剂量标准化血浆C_谷表明在每公斤 BW 基础上两个物种之间的药代动力学特征和组织分布相似。总之，人类 CL 和血浆C_谷（组织分布的替代物）可以通过 BW 在 mg/kg 剂量基础上从猴子直接预测（1:1 或两倍以内），但这些参数可能被低估或高估通过 BSA 在 mg/m ²剂量的基础上。这些结果为单一物种从猴子直接扩展到人类提供了证据，因此，它们可以促进 ASO 药物开发中的早期人类剂量预测。