Department of Pharmacy, Peking University People's Hospital, Beijing, China.
Faculty of Life Sciences and Biopharmaceuticals, Shenyang Pharmceutical University, Shenyang, China.
Front Immunol. 2022 Aug 2;13:871372. doi: 10.3389/fimmu.2022.871372. eCollection 2022.
A number of population pharmacokinetic (PPK) models of anti-programmed cell death-1 (PD-1) monoclonal antibodies (mAbs) in multiple tumor types have been published to characterize the influencing factors of their pharmacokinetics. This review described PPK models of anti-PD-1 mAbs that investigate the magnitude and types of covariate effects in PK parameters, provide a reference for building PPK models of other anti-PD-1 mAbs, and identify areas requiring additional research to facilitate the application of PPK models.
A systematic search for analyses of PPK models of eleven anti-PD-1 mAbs on the market that were carried out in humans was conducted using PubMed, Embase, and the Cochrane Library. The search covered the period from the inception of the databases to April 2022.
Currently, there are fourteen analyses on PPK models of anti-PD-1 mAbs summarized in this review, including seven models that refer to nivolumab, four referring to pembrolizumab, one referring to cemiplimab, one referring to camrelizumab, and one referred to dostarlimab. Most analyses described the pharmacokinetics of anti-PD-1 mAbs with a two-compartment model with time-varying clearance (CL) and a sigmoidal maximum effect. The estimated CL and volume of distribution in the central (V) ranged from 0.179 to 0.290 L/day and 2.98 to 4.46 L, respectively. The median (range) of interindividual variability (IIV) for CL and V was 30.9% (8.7%-50.8%) and 29.0% (4.32%-40.7%), respectively. The commonly identified significant covariates were body weight (BW) on CL and V, and albumin (ALB), tumor type, sex, and performance status (PS) on CL. Other less assessed significant covariates included lactate dehydrogenase (LDH), immunoglobulin G (IgG), ipilimumab coadministration (IPICO) on CL, and body mass index (BMI), malignant pleural mesothelioma (MESO) on V.
This review provides detailed information about the characteristics of PPK models of anti-PD-1 mAbs, the effects of covariates on PK parameters, and the current status of the application of the models. ALB, BW, specific tumor type, sex, and PS should be considered for the future development of the PPK model of anti-PD-1 mAbs. Other potential covariates that were assessed less frequently but still have significance (e.g., LDH, IgG, and IPICO) should not be ignored. Thus, further research and thorough investigation are needed to assess new or potential covariates, which will pave the way for personalized anti-PD-1 mAbs therapy.
已有多项针对多种肿瘤类型的抗程序性细胞死亡-1（PD-1）单克隆抗体（mAb）的群体药代动力学（PPK）模型发表，用于描述药代动力学的影响因素。本综述描述了抗 PD-1 mAb 的 PPK 模型，这些模型探讨了药代动力学参数中协变量效应的大小和类型，为其他抗 PD-1 mAb 的 PPK 模型构建提供了参考，并确定了需要进一步研究的领域，以促进 PPK 模型的应用。
使用 PubMed、Embase 和 Cochrane Library 对已发表的市场上 11 种抗 PD-1 mAb 的 PPK 模型分析进行了系统性检索。检索范围从数据库建立到 2022 年 4 月。
目前，本综述共总结了 14 项抗 PD-1 mAb 的 PPK 模型分析，其中包括 7 项关于 nivolumab 的模型、4 项关于 pembrolizumab 的模型、1 项关于 cemiplimab 的模型、1 项关于 camrelizumab 的模型和 1 项关于 dostarlimab 的模型。大多数分析描述了抗 PD-1 mAb 的药代动力学，采用具有时变清除率（CL）和最大效应的二室模型。估计的 CL 和中央（V）分布容积分别在 0.179 至 0.290 L/天和 2.98 至 4.46 L 之间。CL 和 V 的个体间变异（IIV）中位数（范围）分别为 30.9%（8.7%-50.8%）和 29.0%（4.32%-40.7%）。常见的显著协变量包括 CL 和 V 上的体重（BW）和白蛋白（ALB）、肿瘤类型、性别和表现状态（PS）。其他评估较少的显著协变量包括乳酸脱氢酶（LDH）、免疫球蛋白 G（IgG）、伊匹单抗联合治疗（IPICO）上的 CL 和身体质量指数（BMI）、恶性胸膜间皮瘤（MESO）上的 V。
本综述提供了抗 PD-1 mAb 的 PPK 模型特征、协变量对 PK 参数的影响以及模型应用现状的详细信息。未来抗 PD-1 mAb 的 PPK 模型应考虑 ALB、BW、特定肿瘤类型、性别和 PS。其他评估较少但仍具有意义的潜在协变量（例如 LDH、IgG 和 IPICO）不应忽视。因此，需要进一步研究和深入调查以评估新的或潜在的协变量，为个体化抗 PD-1 mAb 治疗铺平道路。
