免疫检查点抑制剂药动学和药效学的关系

Relationship Between the Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors

免疫检查点抑制剂是针对负免疫调节因子的单克隆抗体,用于恢复机体对恶性肿瘤的免疫反应。目前,批准使用的药物包括毒性T淋巴细胞相关抗原4(cytotoxic T-lymphocyte antigen 4,CTLA-4)抑制剂、程序性细胞死亡蛋白受体1(programmed cell death 1,PD-1)抑制剂和程序性细胞死亡蛋白配体1(programmed cell death-ligand 1,PD-L1)抑制剂,上述药物均具备典型的单克隆抗体的药动学特征,如年龄、性别、种族和肿瘤负荷等因素均不影响药物的清除,但体重除外。有研究结果表明,CTLA-4抑制剂、PD-1抑制剂的疗效、毒性存在暴露-反应关系。已有研究结果证实,纳武利尤单抗、帕博利珠单抗的清除率随时间的变化与总体疗效相关;PD-L1抑制剂的药动学和药效学相关研究数据甚少,但是其清除率随时间的变化是明确的,其中阿特珠单抗免疫原性高,可能会影响药动学参数,需进一步研究。本文总结了免疫检查点抑制剂相关药动学的研究,探讨可能影响其药动学的因素和规律,探究对相关药物进行治疗药物监测的意义。

Immune checkpoint inhibitors are monoclonal antibodies against negative immunomodulatory factor,which is used to restore body’s immune response against malignant tumors.At present,the approved drugs include cytotoxic T-lymphocyte antigen 4(CTLA-4)inhibitor,programmed cell death 1(PD-1)inhibitor and programmed cell death-ligand 1(PD-L1)inhibitor,all the above drugs have typical pharmacokinetics characteristics of monoclonal antibodies,such as age,gender,race and tumor load that have no effects on the elimination of drug,except for body weight.Studies have shown that there is an exposure-response relationship in the efficacy and toxicity of CTLA-4 inhibitor and PD-1 inhibitor.Existing research results have confirmed that the clearance rates of Nivolumab and Pembrolizumab over time is related to the overall efficacy;there are few research data about the pharmacokinetics and pharmacodynamics of PD-L1 inhibitors,but it’s clearance rate has specific variation over time,of which the Atezolizumab has high immunogenicity that may affect pharmacokinetics parameters and needs further study.This article has summarized related research on the pharmacokinetics of immune checkpoint inhibitors,explored the factors and rules that may affect its pharmacokinetics,and explored the significance of therapeutic drug monitoring for related drugs.