A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics
A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics
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DOI：
10.1208/s12248-013-9517-z
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发表时间：
2013-10-01
期刊：
影响因子：
4.5
通讯作者：
Vicini, Paolo
中科院分区：
文献类型：
--
作者：
Chen, Xiaoying;Hickling, Timothy;Vicini, Paolo
构建数学药代动力学/抗药抗体（PK/ADA）模型，用于定量评估治疗性蛋白质的免疫原性。该模型受传统药代动力学/药效学（PK/PD）模型的启发，并基于观察到的ADA对蛋白质药物清除率的影响。这项工作的假设是，改变的药物PK包含有关ADA生成的程度和时间的信息。通过拟合药物PK特征，同时考虑ADA介导的药物清除率，该模型提供了一种表征研究期间ADA生成的方法，包括最大ADA应答、ADA应答对药物剂量水平的敏感性、亲和力成熟率、观察ADA应答的时滞和ADA-药物复合物的消除率。该模型还提供了估计ADA、ADA-药物复合物和ADA结合亲和力-时间曲线的推定浓度-时间曲线的平均值。当模拟ADA对不同药物剂量水平的反应时，生成钟形剂量-反应曲线。该模型包含同时定量建模，并提供了体内治疗性蛋白质药物PK和ADA应答特征的估计。通过进一步的实验验证，该模型可以应用于计算机模拟ADA对治疗性蛋白质药物的反应，或应用于后续的PK/PD模型。
A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA-mediated drug clearance, the model provides an approach to characterize ADA generation during the study, including the maximum ADA response, sensitivity of ADA response to drug dose level, affinity maturation rate, time lag to observe an ADA response, and the elimination rate for ADA-drug complex. The model also provides a mean to estimate putative concentration-time profiles for ADA, ADA-drug complex, and ADA binding affinity-time profile. When simulating ADA responses to various drug dose levels, bell-shaped dose-response curves were generated. The model contains simultaneous quantitative modeling and provides estimation of the characteristics of therapeutic protein drug PK and ADA responses in vivo. With further experimental validation, the model may be applied to the simulation of ADA response to therapeutic protein drugs in silico, or be applied in subsequent PK/PD models.