{"title":"General quasi-equilibrium multivalent binding model to study diverse and complex drug-receptor interactions of biologics.","authors":"Chee M Ng, Robert J Bauer","doi":"10.1007/s10928-024-09936-5","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"841-857"},"PeriodicalIF":2.2000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pharmacokinetics and Pharmacodynamics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10928-024-09936-5","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/17 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
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.