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Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects
The gut wall consists of many biological elements, including enterocytes. Rapid turnover, a prominent feature of the enterocytes, has generally been ignored in the development of enterocyte‐targeting drugs, although it has a comparable rate to other kinetic rates. Here, we investigated the impact of...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679071/ https://www.ncbi.nlm.nih.gov/pubmed/32989926 http://dx.doi.org/10.1002/psp4.12557 |
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author | Takita, Hiroyuki Darwich, Adam S. Ahmad, Amais Rostami‐Hodjegan, Amin |
author_facet | Takita, Hiroyuki Darwich, Adam S. Ahmad, Amais Rostami‐Hodjegan, Amin |
author_sort | Takita, Hiroyuki |
collection | PubMed |
description | The gut wall consists of many biological elements, including enterocytes. Rapid turnover, a prominent feature of the enterocytes, has generally been ignored in the development of enterocyte‐targeting drugs, although it has a comparable rate to other kinetic rates. Here, we investigated the impact of enterocyte turnover on the pharmacodynamics of enterocyte‐targeting drugs by applying a model accounting for turnover of enterocytes and target proteins. Simulations showed that the pharmacodynamics depend on enterocyte lifespan when drug‐target affinity is strong and half‐life of target protein is long. Interindividual variability of enterocyte lifespan, which can be amplified by disease conditions, has a substantial impact on the variability of response. However, our comprehensive literature search showed that the enterocyte turnover causes a marginal impact on currently approved enterocyte‐targeting drugs due to their relatively weak target affinities. This study proposes a model‐informed drug development approach for selecting enterocyte‐targeting drugs and their optimal dosage regimens. |
format | Online Article Text |
id | pubmed-7679071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76790712020-11-27 Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects Takita, Hiroyuki Darwich, Adam S. Ahmad, Amais Rostami‐Hodjegan, Amin CPT Pharmacometrics Syst Pharmacol Research The gut wall consists of many biological elements, including enterocytes. Rapid turnover, a prominent feature of the enterocytes, has generally been ignored in the development of enterocyte‐targeting drugs, although it has a comparable rate to other kinetic rates. Here, we investigated the impact of enterocyte turnover on the pharmacodynamics of enterocyte‐targeting drugs by applying a model accounting for turnover of enterocytes and target proteins. Simulations showed that the pharmacodynamics depend on enterocyte lifespan when drug‐target affinity is strong and half‐life of target protein is long. Interindividual variability of enterocyte lifespan, which can be amplified by disease conditions, has a substantial impact on the variability of response. However, our comprehensive literature search showed that the enterocyte turnover causes a marginal impact on currently approved enterocyte‐targeting drugs due to their relatively weak target affinities. This study proposes a model‐informed drug development approach for selecting enterocyte‐targeting drugs and their optimal dosage regimens. John Wiley and Sons Inc. 2020-09-28 2020-11 /pmc/articles/PMC7679071/ /pubmed/32989926 http://dx.doi.org/10.1002/psp4.12557 Text en © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Takita, Hiroyuki Darwich, Adam S. Ahmad, Amais Rostami‐Hodjegan, Amin Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects |
title | Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects |
title_full | Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects |
title_fullStr | Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects |
title_full_unstemmed | Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects |
title_short | Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects |
title_sort | application of the nested enzyme‐within‐enterocyte (newe) turnover model for predicting the time course of pharmacodynamic effects |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679071/ https://www.ncbi.nlm.nih.gov/pubmed/32989926 http://dx.doi.org/10.1002/psp4.12557 |
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