University Paris-Saclay, Faculty of Pharmacy, Chatenay-Malabry, F-92290, France; Gustave Roussy Cancer Campus, Laboratory of Immunomonitoring in Oncology, Villejuif, F-94805, France.
Gustave Roussy Cancer Campus, Department of Pharmacology, Villejuif, F-94805, France.
Eur J Cancer. 2020 Mar;128:119-128. doi: 10.1016/j.ejca.2020.01.003. Epub 2020 Feb 6.
Immune checkpoint inhibitors are monoclonal antibodies (mAbs) directed against negative immunologic regulators that are used to restore the immune response against cancer. Approved drugs include anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) antibodies exhibiting pharmacokinetic (PK) characteristics typical of mAbs. Most factors such as age, sex, ethnicity, tumour burden, performance status and immunogenicity, but not body weight, do not seem to affect drug clearance clinically. However, an exposure-response relation has been described for both the efficacy and toxicity of anti-CTLA-4 and anti-PD-1 agents. The change in clearance over time is associated with overall response at least for nivolumab and pembrolizumab. Few PK/pharmacodynamic (PD) data are available for anti-PD-L1 mAbs, but time-varying clearance has been described for these drugs, and the high immunogenicity rate observed with atezolizumab may affect PK parameters and should be further studied. These data suggest the need for additional PK/PD studies. In this review, we summarise studies of the PKs of immune checkpoint inhibitors, exploring possible interactions with PD considerations.
免疫检查点抑制剂是一种针对负性免疫调节因子的单克隆抗体（mAbs），用于恢复针对癌症的免疫反应。已批准的药物包括抗细胞毒性 T 淋巴细胞抗原 4（CTLA-4）、抗程序性细胞死亡 1（PD-1）和抗程序性细胞死亡配体 1（PD-L1）抗体，具有 mAbs 的典型药代动力学（PK）特征。大多数因素，如年龄、性别、种族、肿瘤负担、表现状态和免疫原性，但不是体重，似乎不会对药物清除率产生临床影响。然而，已经描述了抗 CTLA-4 和抗 PD-1 药物的疗效和毒性的暴露-反应关系。清除率随时间的变化与至少对于 nivolumab 和 pembrolizumab 的总体反应相关。对于抗 PD-L1 mAbs，只有少数 PK/药效动力学（PD）数据可用，但已经描述了这些药物的时变清除率，atezolizumab 观察到的高免疫原性可能会影响 PK 参数，应进一步研究。这些数据表明需要进行额外的 PK/PD 研究。在这篇综述中，我们总结了免疫检查点抑制剂的 PK 研究，探讨了与 PD 考虑因素的可能相互作用。
