Hansen Aaron R, Cook Natalie, Ricci M Stacey, Razak Albiruni, Le Tourneau Christophe, McKeever Kathleen, Roskos Lorin, Dixit Rakesh, Siu Lillian L, Hinrichs Mary Jane
Drug Development Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Division of Hematology and Oncology Toxicology, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA; Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France; INSERM U900, Institut Curie, Paris, France; Translational Sciences, MedImmune LLC, Gaithersburg, Maryland, USA.
Drug Development Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Division of Hematology and Oncology Toxicology, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA; Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France; INSERM U900, Institut Curie, Paris, France; Translational Sciences, MedImmune LLC, Gaithersburg, Maryland, USA
Oncologist. 2015 Jun;20(6):653-9. doi: 10.1634/theoncologist.2015-0008. Epub 2015 May 11.
First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs).
A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial.
The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8-500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5-55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD.
One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials.
Start dose (SD) for biotechnology-derived products (BDPs) can be safely derived from one-sixth the highest nonseverely toxic dose in nonrodent species and may reduce the number of dose escalations needed to reach the recommended dose in first-in-human studies while limiting unnecessary exposure to high drug levels in humans. The use of this type of SD could improve the design of phase I studies of BDPs by making them more efficient. The role of preclinical pharmacodynamic markers was useful in confirming the hypothetical SD, and attempts should be explored in future animal studies to identify such parameters.
低分子量抗癌药物的首次人体试验通常从啮齿动物10%的严重毒性剂量的十分之一或非啮齿动物物种的最高非严重毒性剂量（HNSTD）的六分之一得出安全起始剂量（SD）。对于这种范例是否可以安全应用于生物技术衍生产品（BDP），尚未达成共识。
进行全面检索，以识别所有具有足够非临床和临床数据的BDP（不包括免疫检查点抑制剂和抗体药物偶联物），以评估在晚期癌症首次人体试验中假设使用六分之一HNSTD的安全性。
检索识别出23种BDP，其中21种是单克隆抗体。最大耐受剂量或最大给药剂量（MTD或MAD）与实际首次人体试验SD的中位数比值为36（范围为8 - 500）。只有2种BDP达到了MTD。假设使用六分之一HNSTD（按比例换算至人体）对所有23种BDP都不会超过MTD或MAD，并且会将MTD或MAD与SD的中位数比值降至6.1（范围为3.5 - 55.3）。一些动物毒理学研究纳入了药效学（PD）标志物，有助于确认六分之一HNSTD的假设SD。
根据现有数据，六分之一HNSTD不会导致不可接受的毒性。支持使用该剂量可以减少达到推荐剂量所需的剂量递增次数。动物和人类中低毒性发生率强调了识别药代动力学和PD参数以指导BDP在首次人体癌症试验中选择SD的必要性。
生物技术衍生产品（BDP）的起始剂量（SD）可以安全地从非啮齿动物物种的最高非严重毒性剂量的六分之一得出，并且可能减少在首次人体研究中达到推荐剂量所需的剂量递增次数，同时限制人体不必要地暴露于高药物水平。使用这种类型的SD可以通过提高效率来改善BDP的I期研究设计。临床前药效学标志物在确认假设SD方面很有用，未来的动物研究应探索确定此类参数的方法。
