Validity conditions of approximations for a target-mediated drug disposition model : A novel first-order approximation and its comparison to other approximations
Copyright: © 2024 Byun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited..
Target-mediated drug disposition (TMDD) is a phenomenon characterized by a drug's high-affinity binding to a target molecule, which significantly influences its pharmacokinetic profile within an organism. The comprehensive TMDD model delineates this interaction, yet it may become overly complex and computationally demanding in the absence of specific concentration data for the target or its complexes. Consequently, simplified TMDD models employing quasi-steady state approximations (QSSAs) have been introduced; however, the precise conditions under which these models yield accurate results require further elucidation. Here, we establish the validity of three simplified TMDD models: the Michaelis-Menten model reduced with the standard QSSA (mTMDD), the QSS model reduced with the total QSSA (qTMDD), and a first-order approximation of the total QSSA (pTMDD). Specifically, we find that mTMDD is applicable only when initial drug concentrations substantially exceed total target concentrations, while qTMDD can be used for all drug concentrations. Notably, pTMDD offers a simpler and faster alternative to qTMDD, with broader applicability than mTMDD. These findings are confirmed with antibody-drug conjugate real-world data. Our findings provide a framework for selecting appropriate simplified TMDD models while ensuring accuracy, potentially enhancing drug development and facilitating safer, more personalized treatments.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
PLoS computational biology - 20(2024), 4 vom: 02. Apr., Seite e1012066 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Byun, Jong Hyuk [VerfasserIn] |
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| Links: |
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| Themen: |
Comparative Study |
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| Anmerkungen: |
Date Completed 13.05.2024 Date Revised 15.05.2024 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.pcbi.1012066 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM371458560 |
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| 245 | 1 | 0 | |a Validity conditions of approximations for a target-mediated drug disposition model |b A novel first-order approximation and its comparison to other approximations |
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| 500 | |a Date Revised 15.05.2024 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright: © 2024 Byun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||
| 520 | |a Target-mediated drug disposition (TMDD) is a phenomenon characterized by a drug's high-affinity binding to a target molecule, which significantly influences its pharmacokinetic profile within an organism. The comprehensive TMDD model delineates this interaction, yet it may become overly complex and computationally demanding in the absence of specific concentration data for the target or its complexes. Consequently, simplified TMDD models employing quasi-steady state approximations (QSSAs) have been introduced; however, the precise conditions under which these models yield accurate results require further elucidation. Here, we establish the validity of three simplified TMDD models: the Michaelis-Menten model reduced with the standard QSSA (mTMDD), the QSS model reduced with the total QSSA (qTMDD), and a first-order approximation of the total QSSA (pTMDD). Specifically, we find that mTMDD is applicable only when initial drug concentrations substantially exceed total target concentrations, while qTMDD can be used for all drug concentrations. Notably, pTMDD offers a simpler and faster alternative to qTMDD, with broader applicability than mTMDD. These findings are confirmed with antibody-drug conjugate real-world data. Our findings provide a framework for selecting appropriate simplified TMDD models while ensuring accuracy, potentially enhancing drug development and facilitating safer, more personalized treatments | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Comparative Study | |
| 650 | 7 | |a Pharmaceutical Preparations |2 NLM | |
| 700 | 1 | |a Jeon, Hye Seon |e verfasserin |4 aut | |
| 700 | 1 | |a Yun, Hwi-Yeol |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Jae Kyoung |e verfasserin |4 aut | |
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