Saber Haleh, Gudi Ramadevi, Manning Michael, Wearne Emily, Leighton John K
US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States.
US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States.
Regul Toxicol Pharmacol. 2016 Nov;81:448-456. doi: 10.1016/j.yrtph.2016.10.002. Epub 2016 Oct 13.
As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities. For approximately half the antibodies (44%) examined, the FIH doses were at least a hundred-fold lower than the doses safely administered to patients, indicating optimization of FIH dose selection and/or optimization of dose-finding trial design is needed to minimize patient exposure to sub-therapeutic doses. However, selection of the FIH dose for antibodies based on animal toxicology studies using 1/6th the HNSTD or 1/10th the NOAEL resulted in human doses that were unsafe for several antibodies examined. We also concluded that antibodies with Fc-modifications for increased effector function may be less tolerated, resulting in toxicities at lower doses than those without such modifications. There was insufficient information to evaluate CD3 bispecific products.
由于亚治疗剂量对癌症患者在医学上不合理，我们回顾性分析了免疫激活产品的数据，以评估首次人体（FIH）剂量选择中使用的方法、动物毒理学研究在剂量选择中的效用以及完成FIH试验的时间长度。收集的信息包括药理学和毒理学数据、FIH剂量及理由，以及剂量探索试验设计。我们使用希尔方程的原理来估计抗体的FIH剂量，并将其与给予具有可接受毒性的患者的剂量进行比较。对于大约一半（44%）检测的抗体，FIH剂量比安全给予患者的剂量至少低一百倍，这表明需要优化FIH剂量选择和/或优化剂量探索试验设计，以尽量减少患者暴露于亚治疗剂量。然而，基于使用六分之一的人等效剂量（HNSTD）或十分之一的无观察到不良反应水平（NOAEL）的动物毒理学研究来选择抗体的FIH剂量，导致对于几种检测的抗体，人体剂量不安全。我们还得出结论，具有增强效应功能的Fc修饰的抗体可能耐受性较差，导致在比没有此类修饰的抗体更低的剂量下出现毒性。评估CD3双特异性产品的信息不足。
