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In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned

Physiologically based kinetic (PBK) modeling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, howeve...

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Autores principales: Algharably, Engi Abdelhady, Di Consiglio, Emma, Testai, Emanuela, Pistollato, Francesca, Mielke, Hans, Gundert-Remy, Ursula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340473/
https://www.ncbi.nlm.nih.gov/pubmed/35924078
http://dx.doi.org/10.3389/ftox.2022.885843
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author Algharably, Engi Abdelhady
Di Consiglio, Emma
Testai, Emanuela
Pistollato, Francesca
Mielke, Hans
Gundert-Remy, Ursula
author_facet Algharably, Engi Abdelhady
Di Consiglio, Emma
Testai, Emanuela
Pistollato, Francesca
Mielke, Hans
Gundert-Remy, Ursula
author_sort Algharably, Engi Abdelhady
collection PubMed
description Physiologically based kinetic (PBK) modeling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, however, to a smaller extent, although an internationally agreed document was published already in 2010 (IPCS/WHO), but at that time, PBK modeling was based mostly on in vivo data as the example in the IPCS/WHO document indicates. Recently, the OECD has published a guidance document which set standards on how to characterize, validate, and report PBK models for regulatory purposes. In the past few years, we gained experience on using in vitro data for performing quantitative in vitro–in vivo extrapolation (QIVIVE), in which biokinetic data play a crucial role to obtain a realistic estimation of human exposure. In addition, pharmaco-/toxicodynamic aspects have been introduced into the approach. Here, three examples with different drugs/chemicals are described, in which different approaches have been applied. The lessons we learned from the exercise are as follows: 1) in vitro conditions should be considered and compared to the in vivo situation, particularly for protein binding; 2) in vitro inhibition of metabolizing enzymes by the formed metabolites should be taken into consideration; and 3) it is important to extrapolate from the in vitro measured intracellular concentration and not from the nominal concentration to the tissue/organ concentration to come up with an appropriate QIVIVE for the relevant adverse effects.
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spelling pubmed-93404732022-08-02 In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned Algharably, Engi Abdelhady Di Consiglio, Emma Testai, Emanuela Pistollato, Francesca Mielke, Hans Gundert-Remy, Ursula Front Toxicol Toxicology Physiologically based kinetic (PBK) modeling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, however, to a smaller extent, although an internationally agreed document was published already in 2010 (IPCS/WHO), but at that time, PBK modeling was based mostly on in vivo data as the example in the IPCS/WHO document indicates. Recently, the OECD has published a guidance document which set standards on how to characterize, validate, and report PBK models for regulatory purposes. In the past few years, we gained experience on using in vitro data for performing quantitative in vitro–in vivo extrapolation (QIVIVE), in which biokinetic data play a crucial role to obtain a realistic estimation of human exposure. In addition, pharmaco-/toxicodynamic aspects have been introduced into the approach. Here, three examples with different drugs/chemicals are described, in which different approaches have been applied. The lessons we learned from the exercise are as follows: 1) in vitro conditions should be considered and compared to the in vivo situation, particularly for protein binding; 2) in vitro inhibition of metabolizing enzymes by the formed metabolites should be taken into consideration; and 3) it is important to extrapolate from the in vitro measured intracellular concentration and not from the nominal concentration to the tissue/organ concentration to come up with an appropriate QIVIVE for the relevant adverse effects. Frontiers Media S.A. 2022-07-18 /pmc/articles/PMC9340473/ /pubmed/35924078 http://dx.doi.org/10.3389/ftox.2022.885843 Text en Copyright © 2022 Algharably, Di Consiglio, Testai, Pistollato, Mielke and Gundert-Remy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Toxicology
Algharably, Engi Abdelhady
Di Consiglio, Emma
Testai, Emanuela
Pistollato, Francesca
Mielke, Hans
Gundert-Remy, Ursula
In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned
title In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned
title_full In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned
title_fullStr In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned
title_full_unstemmed In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned
title_short In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned
title_sort in vitro–in vivo extrapolation by physiologically based kinetic modeling: experience with three case studies and lessons learned
topic Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340473/
https://www.ncbi.nlm.nih.gov/pubmed/35924078
http://dx.doi.org/10.3389/ftox.2022.885843
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