通用准平衡多价结合模型,用于研究生物制剂的各种复杂的药物-受体相互作用。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Chee M Ng, Robert J Bauer
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引用次数: 0

摘要

许多生物制剂的药代动力学和药效学受其与生物受体复杂结合的影响。生物制剂由不同的分子组组成,这些分子组与受体的结合动力学各不相同,其中包括与药物受体一对一结合的 IgG、与两种不同受体结合的双特异性抗体(BsAb)以及可与六种或六种以上相同受体结合的抗体。由于结合过程通常比消除(或内化)和分布过程快得多,因此准平衡(QE)结合模型常用于描述生物制剂的药物受体结合动力学。然而,目前还没有通用的 QE 模型框架来描述不同类别生物制剂的复杂结合动力学。在本文中,我们介绍了使用微分代数方程(DAE)求解三种 QE 多价药物受体结合(QEMB)模型的新方法。第一个例子描述了与 2 种不同受体结合形成三聚体的 BsAb 的三体平衡结合动力学。第二个例子模拟了可与 24 个相同目标受体结合的工程化 IgG 变异体(多体)。第三个例子描述了一种具有改良新生 Fc 受体(FcRn)结合亲和力的 IgG,它与内源性 IgG 竞争相同的 FcRn 受体。模型参数估计是通过同时拟合所有数据得到的。通过这些模型,我们可以研究合作结合对 BsAb 的钟形药物暴露-反应关系的潜在作用,以及 Multabody 不同药物-受体复合物的浓度依赖性分布。这种基于 DAE 的 QEMB 模型平台可作为一种重要工具,用于更好地理解不同类别生物制剂的复杂结合动力学。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

General quasi-equilibrium multivalent binding model to study diverse and complex drug-receptor interactions of biologics.

General quasi-equilibrium multivalent binding model to study diverse and complex drug-receptor interactions of biologics.

Pharmacokinetics and pharmacodynamics of many biologics are influenced by their complex binding to biological receptors. Biologics consist of diverse groups of molecules with different binding kinetics to its receptors including IgG with simple one-to-one drug receptor bindings, bispecific antibody (BsAb) that binds to two different receptors, and antibodies that can bind to six or more identical receptors. As the binding process is typically much faster than elimination (or internalization) and distribution processes, quasi-equilibrium (QE) binding models are commonly used to describe drug-receptor binding kinetics of biologics. However, no general QE modeling framework is available to describe complex binding kinetics for diverse classes of biologics. In this paper, we describe novel approaches of using differential algebraic equations (DAE) to solve three QE multivalent drug-receptor binding (QEMB) models. The first example describes the binding kinetics of three-body equilibria of BsAb that binds to 2 different receptors for trimer formation. The second example models an engineered IgG variant (Multabody) that can bind to 24 identical target receptors. The third example describes an IgG with modified neonatal Fc receptor (FcRn) binding affinity that competes for the same FcRn receptor as endogenous IgG. The model parameter estimates were obtained by fitting the model to all data simultaneously. The models allowed us to study potential roles of cooperative binding on bell-shaped drug exposure-response relationships of BsAb, and concentration-depended distribution of different drug-receptor complexes for Multabody. This DAE-based QEMB model platform can serve as an important tool to better understand complex binding kinetics of diverse classes of biologics.

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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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