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A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies

In drug discovery, the emergence of unexpected toxicity is often a problem resulting from a poor understanding of the pharmacokinetics of drug–drug interactions (DDI). Organ-on-a-chip (OoC) has been proposed as an in vitro model to evaluate drug efficacy and toxicity in pharmacology, but it has not...

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Autores principales: Shinha, Kenta, Nihei, Wataru, Ono, Tatsuto, Nakazato, Ryota, Kimura, Hiroshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AIP Publishing LLC 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719524/
https://www.ncbi.nlm.nih.gov/pubmed/34992705
http://dx.doi.org/10.1063/5.0011545
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author Shinha, Kenta
Nihei, Wataru
Ono, Tatsuto
Nakazato, Ryota
Kimura, Hiroshi
author_facet Shinha, Kenta
Nihei, Wataru
Ono, Tatsuto
Nakazato, Ryota
Kimura, Hiroshi
author_sort Shinha, Kenta
collection PubMed
description In drug discovery, the emergence of unexpected toxicity is often a problem resulting from a poor understanding of the pharmacokinetics of drug–drug interactions (DDI). Organ-on-a-chip (OoC) has been proposed as an in vitro model to evaluate drug efficacy and toxicity in pharmacology, but it has not been applied to DDI studies yet. In this study, we aim to evaluate whether organ-on-a-chip technologies can be applied to DDI studies. To assess the usefulness of OoC for DDI studies, we proposed a multi-organ-on-a-chip (MOoC) with a liver part as the metabolic model and a cancer part as the drug target model, and a pharmacokinetic–pharmacodynamic (PK–PD) model describing the MOoC. An anticancer prodrug, CPT-11, was used to evaluate the drug efficacy of the metabolite in the liver part of the MOoC. To evaluate DDI using the MOoC, the inhibitory effect of simvastatin and ritonavir on the metabolism of CPT-11 was tested. The DDI estimation method was evaluated by comparing the results of the concomitant administration experiment using the MOoC and the results of simulation using the proposed PK–PD model with the estimated parameters. The results were similar, suggesting that the combination of the PK–PD model and the MOoC is a useful way to predict DDI. We conclude that OoC technologies could facilitate a better understanding of pharmacokinetic mechanisms with DDI.
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spelling pubmed-87195242022-01-05 A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies Shinha, Kenta Nihei, Wataru Ono, Tatsuto Nakazato, Ryota Kimura, Hiroshi Biomicrofluidics Regular Articles In drug discovery, the emergence of unexpected toxicity is often a problem resulting from a poor understanding of the pharmacokinetics of drug–drug interactions (DDI). Organ-on-a-chip (OoC) has been proposed as an in vitro model to evaluate drug efficacy and toxicity in pharmacology, but it has not been applied to DDI studies yet. In this study, we aim to evaluate whether organ-on-a-chip technologies can be applied to DDI studies. To assess the usefulness of OoC for DDI studies, we proposed a multi-organ-on-a-chip (MOoC) with a liver part as the metabolic model and a cancer part as the drug target model, and a pharmacokinetic–pharmacodynamic (PK–PD) model describing the MOoC. An anticancer prodrug, CPT-11, was used to evaluate the drug efficacy of the metabolite in the liver part of the MOoC. To evaluate DDI using the MOoC, the inhibitory effect of simvastatin and ritonavir on the metabolism of CPT-11 was tested. The DDI estimation method was evaluated by comparing the results of the concomitant administration experiment using the MOoC and the results of simulation using the proposed PK–PD model with the estimated parameters. The results were similar, suggesting that the combination of the PK–PD model and the MOoC is a useful way to predict DDI. We conclude that OoC technologies could facilitate a better understanding of pharmacokinetic mechanisms with DDI. AIP Publishing LLC 2020-07-23 /pmc/articles/PMC8719524/ /pubmed/34992705 http://dx.doi.org/10.1063/5.0011545 Text en © 2020 Author(s). 1932-1058/2020/14(4)/044108/9 https://creativecommons.org/licenses/by/4.0/All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Regular Articles
Shinha, Kenta
Nihei, Wataru
Ono, Tatsuto
Nakazato, Ryota
Kimura, Hiroshi
A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies
title A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies
title_full A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies
title_fullStr A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies
title_full_unstemmed A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies
title_short A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies
title_sort pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies
topic Regular Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719524/
https://www.ncbi.nlm.nih.gov/pubmed/34992705
http://dx.doi.org/10.1063/5.0011545
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