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Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments
Compartmental models which yield linear ordinary differential equations (ODEs) provide common tools for pharmacokinetics (PK) analysis, with exact solutions for drug levels or concentrations readily obtainable for low-dimensional compartment models. Exact solutions enable valuable insights and furth...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979639/ https://www.ncbi.nlm.nih.gov/pubmed/33040255 http://dx.doi.org/10.1007/s10928-020-09719-8 |
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author | Hof, F. Bridge, L. J. |
author_facet | Hof, F. Bridge, L. J. |
author_sort | Hof, F. |
collection | PubMed |
description | Compartmental models which yield linear ordinary differential equations (ODEs) provide common tools for pharmacokinetics (PK) analysis, with exact solutions for drug levels or concentrations readily obtainable for low-dimensional compartment models. Exact solutions enable valuable insights and further analysis of these systems. Transit compartment models are a popular semi-mechanistic approach for generalising simple PK models to allow for delayed kinetics, but computing exact solutions for multi-dosing inputs to transit compartment systems leading to different final compartments is nontrivial. Here, we find exact solutions for drug levels as functions of time throughout a linear transit compartment cascade followed by an absorption compartment and a central blood compartment, for the general case of n transit compartments and M equi-bolus doses to the first compartment. We further show the utility of exact solutions to PK ODE models in finding constraints on equi-dosing regimen parameters imposed by a prescribed therapeutic range. This leads to the construction of equi-dosing regimen regions (EDRRs), providing new, novel visualisations which summarise the safe and effective dosing parameter space. EDRRs are computed for classical and transit compartment models with two- and three-dimensional parameter spaces, and are proposed as useful graphical tools for informing drug dosing regimen design. |
format | Online Article Text |
id | pubmed-7979639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-79796392021-04-05 Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments Hof, F. Bridge, L. J. J Pharmacokinet Pharmacodyn Original Paper Compartmental models which yield linear ordinary differential equations (ODEs) provide common tools for pharmacokinetics (PK) analysis, with exact solutions for drug levels or concentrations readily obtainable for low-dimensional compartment models. Exact solutions enable valuable insights and further analysis of these systems. Transit compartment models are a popular semi-mechanistic approach for generalising simple PK models to allow for delayed kinetics, but computing exact solutions for multi-dosing inputs to transit compartment systems leading to different final compartments is nontrivial. Here, we find exact solutions for drug levels as functions of time throughout a linear transit compartment cascade followed by an absorption compartment and a central blood compartment, for the general case of n transit compartments and M equi-bolus doses to the first compartment. We further show the utility of exact solutions to PK ODE models in finding constraints on equi-dosing regimen parameters imposed by a prescribed therapeutic range. This leads to the construction of equi-dosing regimen regions (EDRRs), providing new, novel visualisations which summarise the safe and effective dosing parameter space. EDRRs are computed for classical and transit compartment models with two- and three-dimensional parameter spaces, and are proposed as useful graphical tools for informing drug dosing regimen design. Springer US 2020-10-10 2021 /pmc/articles/PMC7979639/ /pubmed/33040255 http://dx.doi.org/10.1007/s10928-020-09719-8 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Paper Hof, F. Bridge, L. J. Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments |
title | Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments |
title_full | Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments |
title_fullStr | Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments |
title_full_unstemmed | Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments |
title_short | Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments |
title_sort | exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979639/ https://www.ncbi.nlm.nih.gov/pubmed/33040255 http://dx.doi.org/10.1007/s10928-020-09719-8 |
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