An asymptotic description of a basic FcRn-regulated clearance mechanism and its implications for PBPK modelling of large antibodies.

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-06-24 DOI:10.1007/s10928-024-09925-8
Csaba B Kátai, Shepard J Smithline, Craig J Thalhauser, Sieto Bosgra, Jeroen Elassaiss-Schaap
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Abstract

A basic FcRn-regulated clearance mechanism is investigated using the method of matched asymptotic expansions. The broader aim of the work is to obtain further insight on the mechanism, thereby providing theoretical support for future pharmacologically-based pharmacokinetic modelling efforts. The corresponding governing equations are first non-dimensionalised and the order of magnitudes of the model parameters are assessed based on their values reported in the literature. Under the assumption of high FcRn-binding affinity, analytical approximations are derived that are valid over the characteristic phases of the problem. Additionally, relatively simple equations relating clearance and AUC to physiological model parameters are derived, which are valid over the longest characteristic time scale of the problem. For lower to moderate doses clearance is effectively linear, whereas for higher doses it is nonlinear. It is shown that for all doses sufficiently high the leading-order approximation for the IgG concentration in plasma, over the longest characteristic time scale, is independent of the initial dose. This is because IgG that is in 'excess' of FcRn is eliminated over a time scale much shorter than that of the terminal phase. In conclusion, analytical approximations of the basic FcRn mechanism have been derived using matched asymptotic expansions, leading to a simple equation relating clearance to FcRn binding affinity, the ratio of degradation and FcRn concentration, and the volumes of the system.

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FcRn 调节的基本清除机制的渐近描述及其对大抗体 PBPK 建模的影响。
利用匹配渐近展开法研究了基本的 FcRn 调节清除机制。这项工作的更广泛目标是进一步深入了解该机制,从而为未来基于药理学的药代动力学建模工作提供理论支持。首先对相应的控制方程进行非维度化,并根据文献报道的数值评估模型参数的大小顺序。在高 FcRn 结合亲和力的假设下,得出了在问题的特征阶段有效的分析近似值。此外,还得出了将清除率和 AUC 与生理模型参数联系起来的相对简单的方程,这些方程在问题的最长特征时间尺度上有效。对于低剂量到中等剂量,清除率实际上是线性的,而对于高剂量则是非线性的。研究表明,对于所有足够高的剂量,在最长的特征时间尺度上,血浆中 IgG 浓度的前导近似值与初始剂量无关。这是因为 FcRn "过量 "的 IgG 被消除的时间尺度远远短于终末阶段的时间尺度。总之,我们利用匹配渐近展开法推导出了基本 FcRn 机制的分析近似值,从而得出了一个将清除率与 FcRn 结合亲和力、降解与 FcRn 浓度之比以及系统体积相关联的简单方程。
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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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