Cargando…
Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies
Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910015/ https://www.ncbi.nlm.nih.gov/pubmed/24477089 http://dx.doi.org/10.1038/psp.2013.73 |
_version_ | 1782301923999744000 |
---|---|
author | Li, L Gardner, I Rose, R Jamei, M |
author_facet | Li, L Gardner, I Rose, R Jamei, M |
author_sort | Li, L |
collection | PubMed |
description | Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter values describing binding of trastuzumab to HER2 were largely derived from in vitro data, and the effects of varying HER2 levels, the affinity difference between membrane-bound HER2 and shed antigen, and slow binding kinetics were investigated. The model simulates a sharp decrease in trough drug concentrations at concentrations of soluble target between 500 and 1,000 ng/ml in plasma. This corresponds with the clinical concentration range of soluble target wherein changes in half-life of trastuzumab have been observed. |
format | Online Article Text |
id | pubmed-3910015 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-39100152014-02-03 Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies Li, L Gardner, I Rose, R Jamei, M CPT Pharmacometrics Syst Pharmacol Original Article Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter values describing binding of trastuzumab to HER2 were largely derived from in vitro data, and the effects of varying HER2 levels, the affinity difference between membrane-bound HER2 and shed antigen, and slow binding kinetics were investigated. The model simulates a sharp decrease in trough drug concentrations at concentrations of soluble target between 500 and 1,000 ng/ml in plasma. This corresponds with the clinical concentration range of soluble target wherein changes in half-life of trastuzumab have been observed. Nature Publishing Group 2014-01 2014-01-29 /pmc/articles/PMC3910015/ /pubmed/24477089 http://dx.doi.org/10.1038/psp.2013.73 Text en Copyright © 2014 American Society for Clinical Pharmacology and Therapeutics http://creativecommons.org/licenses/by-nc-nd/3.0/ CPT: Pharmacometrics and Systems Pharmacology is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Li, L Gardner, I Rose, R Jamei, M Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies |
title | Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies |
title_full | Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies |
title_fullStr | Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies |
title_full_unstemmed | Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies |
title_short | Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies |
title_sort | incorporating target shedding into a minimal pbpk–tmdd model for monoclonal antibodies |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910015/ https://www.ncbi.nlm.nih.gov/pubmed/24477089 http://dx.doi.org/10.1038/psp.2013.73 |
work_keys_str_mv | AT lil incorporatingtargetsheddingintoaminimalpbpktmddmodelformonoclonalantibodies AT gardneri incorporatingtargetsheddingintoaminimalpbpktmddmodelformonoclonalantibodies AT roser incorporatingtargetsheddingintoaminimalpbpktmddmodelformonoclonalantibodies AT jameim incorporatingtargetsheddingintoaminimalpbpktmddmodelformonoclonalantibodies |