基于仿真的靶点介导药物处置模型简化分析

doi:10.5246/jcps.2018.11.077

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (11): 767-776.DOI: 10.5246/jcps.2018.11.077

基于仿真的靶点介导药物处置模型简化分析

付毓¹, 姚烨¹, 马培敏², 周绚², 卢炜¹, 周田彦^1*

1. 北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室, 北京 100191
2. 葛兰素史克研发中心, 上海 201203

收稿日期:2018-05-15 修回日期:2018-05-29 出版日期:2018-11-28 发布日期:2018-09-30
通讯作者: Tel.: +86-010-82801717, E-mail: tianyanzhou@bjmu.edu.cn

Simulation-based simplification of target-mediated drug disposition model of denosumab

Yu Fu¹, Ye Yao¹, Peiming Ma², Xuan Zhou², Wei Lu¹, Tianyan Zhou^1*

1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. GSK Research and Development, Shanghai 201203, China

Received:2018-05-15 Revised:2018-05-29 Online:2018-11-28 Published:2018-09-30
Contact: Tel.: +86-010-82801717, E-mail: tianyanzhou@bjmu.edu.cn

摘要/Abstract

摘要：

靶点介导的药物处置模型(Target-mediated drug disposition, TMDD)是研究单克隆抗体非线性PK的主要模型理论之一。然而全量TMDD模型参数较多,有限的临床数据并不能支持模型估算全部参数。因此,本研究旨在通过公式推导和模型仿真探讨TMDD模型的简化方法,提升TMDD模型在有限临床数据建模中的适用性。基于一项关于地诺单抗(denosumab)TMDD模型研究的结果及其模型参数,在群体水平上和个体水平上进行仿真分析。然后,利用准稳态近似模型,在模型拟合和参数估计的稳定性上,检验受体总浓度的两种假设的影响。结果表明,在治疗剂量下,总受体浓度对药物浓度变化的影响很小, 而假设恒定总受体浓度的模型具有相同的预测能力。该简化方法可应用于单抗类药物研发中合理实验设计的制定和最优PK模型的选择。

关键词: 靶点介导的药物处置模型, 单克隆抗体, 非线性药物动力学, 地诺单抗, 仿真

Abstract:

Target-mediated drug disposition (TMDD) model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK) of monoclonal antibodies. However, there are too many parameters in full TMDD model to be estimated based on limited clinical data, leading to instability of the final model. In the present study, we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS) model with the assumption that the total target concentration was a constant parameter during treatment with monoclonal antibody in clinical data modeling. Based on the parameters of a published TMDD model of denosumab, simulations were performed at population and individual levels. Then, a simplified TMDD model, QSS model, was used to examine the effects of hypotheses, in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation. Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses, the total receptor concentration had little influence on changes in drug concentration, and the model with constant total receptor concentration had the same predictive power. The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.

Key words: Target-mediated drug disposition model, Monoclonal antibody, Nonlinear pharmacokinetics, Denosumab, Simulation

中图分类号:

R943.5

Supporting:

Figure S1. Goodness-of-fit plots of R_tot constant model. (A) Simulated observation vs. individual predicted concentration; (B) Observed vs. population predicted concentration; (C) Conditional weighted residual error vs. population predicted concentration; (D) Conditional weighted residual error vs. time after dose.

Figure S2. Goodness-of-fit plots of R_tot variable model. (A) Simulated observation vs. individual predicted concentration; (B) Observed vs. population predicted concentration; (C) Conditional weighted residual error vs. population predicted concentration; (D) Conditional weighted residual error vs. time after dose.

Figure S3. Goodness-of-fit plot of two-compartment model. (A) Simulated observation vs. individual predicted concentration; (B) Observed vs. population predicted concentration; (C) Conditional weighted residual error vs. population predicted concentration; (D) Conditional weighted residual error vs. time after dose.

付毓, 姚烨, 马培敏, 周绚, 卢炜, 周田彦. 基于仿真的靶点介导药物处置模型简化分析[J]. 中国药学(英文版), 2018, 27(11): 767-776.

Yu Fu, Ye Yao, Peiming Ma, Xuan Zhou, Wei Lu, Tianyan Zhou. Simulation-based simplification of target-mediated drug disposition model of denosumab[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(11): 767-776.

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基于仿真的靶点介导药物处置模型简化分析

Simulation-based simplification of target-mediated drug disposition model of denosumab

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