靶介导药物处置(TMDD)再访:TMDD模型的高亲和力与低亲和力近似。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Ronny Straube
{"title":"靶介导药物处置(TMDD)再访:TMDD模型的高亲和力与低亲和力近似。","authors":"Ronny Straube","doi":"10.1002/psp4.70048","DOIUrl":null,"url":null,"abstract":"<p><p>Target-mediated drug disposition (TMDD) is often associated with high-affinity binding to a target resulting in nonlinear pharmacokinetics. For large molecules, such as monoclonal antibodies, this can lead to increased clearance at sub-saturating concentrations. However, for small molecules, target binding can protect the drug from a fast systemic clearance. Here, we show that both types of behaviors can be described by simple expressions arising from a high-affinity approximation of the standard TMDD model. Interestingly, the celebrated Michaelis-Menten (MM) approximation arises in the opposite limit of low affinity and if the systemic drug clearance is sufficiently slow. Our derivation contains a previously missing factor in front of the MM constant that becomes important when target and drug-target complex elimination rates are different. As a measure of target suppression, we also derive simple expressions for the free target to baseline ratio and compare our approximations with data from large and small molecules.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Target-Mediated Drug Disposition (TMDD) Revisited: High Versus Low-Affinity Approximations of the TMDD Model.\",\"authors\":\"Ronny Straube\",\"doi\":\"10.1002/psp4.70048\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Target-mediated drug disposition (TMDD) is often associated with high-affinity binding to a target resulting in nonlinear pharmacokinetics. For large molecules, such as monoclonal antibodies, this can lead to increased clearance at sub-saturating concentrations. However, for small molecules, target binding can protect the drug from a fast systemic clearance. Here, we show that both types of behaviors can be described by simple expressions arising from a high-affinity approximation of the standard TMDD model. Interestingly, the celebrated Michaelis-Menten (MM) approximation arises in the opposite limit of low affinity and if the systemic drug clearance is sufficiently slow. Our derivation contains a previously missing factor in front of the MM constant that becomes important when target and drug-target complex elimination rates are different. As a measure of target suppression, we also derive simple expressions for the free target to baseline ratio and compare our approximations with data from large and small molecules.</p>\",\"PeriodicalId\":10774,\"journal\":{\"name\":\"CPT: Pharmacometrics & Systems Pharmacology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2025-05-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CPT: Pharmacometrics & Systems Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/psp4.70048\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CPT: Pharmacometrics & Systems Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/psp4.70048","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

靶介导的药物处置(TMDD)通常与靶的高亲和力结合相关,导致非线性药代动力学。对于大分子,如单克隆抗体,这可能导致在亚饱和浓度下清除率增加。然而,对于小分子,靶标结合可以保护药物免于快速的全身清除。在这里,我们展示了这两种类型的行为都可以通过由标准TMDD模型的高亲和近似产生的简单表达式来描述。有趣的是,著名的Michaelis-Menten (MM)近似出现在低亲和力的相反极限,如果全身药物清除足够慢。我们的推导包含了先前在MM常数前面缺失的因子,当靶标和药物靶标复合物消除率不同时,该因子变得重要。作为靶抑制的度量,我们还推导了自由靶与基线比的简单表达式,并将我们的近似与大分子和小分子的数据进行了比较。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Target-Mediated Drug Disposition (TMDD) Revisited: High Versus Low-Affinity Approximations of the TMDD Model.

Target-mediated drug disposition (TMDD) is often associated with high-affinity binding to a target resulting in nonlinear pharmacokinetics. For large molecules, such as monoclonal antibodies, this can lead to increased clearance at sub-saturating concentrations. However, for small molecules, target binding can protect the drug from a fast systemic clearance. Here, we show that both types of behaviors can be described by simple expressions arising from a high-affinity approximation of the standard TMDD model. Interestingly, the celebrated Michaelis-Menten (MM) approximation arises in the opposite limit of low affinity and if the systemic drug clearance is sufficiently slow. Our derivation contains a previously missing factor in front of the MM constant that becomes important when target and drug-target complex elimination rates are different. As a measure of target suppression, we also derive simple expressions for the free target to baseline ratio and compare our approximations with data from large and small molecules.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信