One of the key questions for nearly all oligonucleotide therapeutic programs is how to properly extrapolate no-observed adverse effect levels (NOAELs) identified in nonclinical (animal) toxicity studies to the human equivalent dose to enable selection of an appropriate safe starting dose level in normal subjects or patients. There is a strong historical precedent, mainly driven by a guidance document issued from the U.S. Food and Drug Administration, for converting NOAELs expressed as milligram per kilogram body weight (mg/kg) to an NOAEL based on body surface area (BSA), often referred to as allometric scaling. This conversion imparts an additional safety factor of variable magnitude, depending on the species from which the NOAEL has been characterized. The primary impetus for the application of BSA-based dose extrapolation across species derives from cross-species comparisons of the sensitivity to small-molecule anticancer agents and other small-molecule drugs, for which poor predictivity of human sensitivity was obtained with direct extrapolation of mg/kg dose levels and for which much better predictivity was obtained when doses were converted to BSA (mg/m2). The primary question that is raised in the discussion presented herein is whether that widely used allometric scaling paradigm is broadly applicable to all oligonucleotide therapeutics and whether the adherence to this paradigm might result in the unnecessary administration of subpharmacologic doses to initial patient cohorts with life-threatening or severe disease conditions.

中文翻译：

---

非临床毒性研究中所用的寡核苷酸剂量水平外推至人类临床试验中安全起始剂量水平的选择。

几乎所有寡核苷酸治疗计划的关键问题之一是如何正确地将非临床（动物）毒性研究中确定的未观察到的不良反应水平（NOAEL）外推至人的等效剂量，从而能够选择正常的适当安全起始剂量水平受试者或患者。历史上有一个很强的先例，主要是由美国食品和药物管理局发布的指导文件推动的，通常是将基于身体表面积（BSA）的毫克/千克体重（mg / kg）表示的NOAEL转换为NOAEL。称为异度缩放。取决于NOAEL所表征的物种，这种转换可提供可变大小的附加安全系数。基于BSA的剂量外推法在物种间应用的主要动力来自对小分子抗癌药和其他小分子药物的敏感性的跨物种比较，通过对这些因子的直接外推法，人类敏感性的可预测性较差/ kg剂量水平，当剂量转换为BSA（mg / m2）时可获得更好的可预测性。本文提出的讨论中提出的主要问题是，广泛使用的异速伸缩定标范式是否可广泛适用于所有寡核苷酸治疗，是否坚持该范式可能会导致不必要的亚药剂量给具有生命危险的初始患者队列或严重的疾病状况。