Simplification of complex physiologically based pharmacokinetic models of monoclonal antibodies
Monoclonal antibodies (mAbs) exhibit biexponential profiles in plasma that are commonly described with a standard two-compartment model with elimination from the central compartment. These models adequately describe mAb plasma PK. However, these models ignore elimination from the peripheral compartment. This may lead to underestimation of the volume of distribution of the peripheral compartment and thus over-predicts concentration in the peripheral compartment. We developed a simple and physiologically relevant model that incorporates information on binding and dissociation rates between mAb and FcRn receptor, mAb uptake, reflection, and catabolic degradation. We employed a previously published PBPK model and, with assumptions regarding rates of processes controlling mAb disposition, reduced the complex PBPK model to a simpler circular model with central, peripheral, and lymph compartments specifying elimination from both central and peripheral. We successfully applied the model to describe the PK of an investigational mAb. Our model presents an improvement over standard two-compartmental models in predicting whole-body average tissue concentrations while adequately describing plasma PK with minimal complexity and physiologically more meaningful parameters.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
The AAPS journal - 16(2014), 4 vom: 25. Juli, Seite 810-42 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Elmeliegy, Mohamed [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Monoclonal |
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| Anmerkungen: |
Date Completed 06.02.2015 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1208/s12248-014-9591-x |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM238644235 |
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| 100 | 1 | |a Elmeliegy, Mohamed |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Simplification of complex physiologically based pharmacokinetic models of monoclonal antibodies |
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| 500 | |a Date Completed 06.02.2015 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Monoclonal antibodies (mAbs) exhibit biexponential profiles in plasma that are commonly described with a standard two-compartment model with elimination from the central compartment. These models adequately describe mAb plasma PK. However, these models ignore elimination from the peripheral compartment. This may lead to underestimation of the volume of distribution of the peripheral compartment and thus over-predicts concentration in the peripheral compartment. We developed a simple and physiologically relevant model that incorporates information on binding and dissociation rates between mAb and FcRn receptor, mAb uptake, reflection, and catabolic degradation. We employed a previously published PBPK model and, with assumptions regarding rates of processes controlling mAb disposition, reduced the complex PBPK model to a simpler circular model with central, peripheral, and lymph compartments specifying elimination from both central and peripheral. We successfully applied the model to describe the PK of an investigational mAb. Our model presents an improvement over standard two-compartmental models in predicting whole-body average tissue concentrations while adequately describing plasma PK with minimal complexity and physiologically more meaningful parameters | ||
| 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 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 700 | 1 | |a Lowe, Philip |e verfasserin |4 aut | |
| 700 | 1 | |a Krzyzanski, Wojciech |e verfasserin |4 aut | |
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