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Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection

Here, we evaluate protocol requirements to mimic therapeutically relevant drug concentrations at the site of infection (i.e. lung lesion) in an in-vitro hollow fibre model of infection using pulmonary tuberculosis as a paradigm. Steady-state pharmacokinetic profiles in plasma, lung tissue and lung l...

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Autores principales: Kloprogge, Frank, Hammond, Robert, Kipper, Karin, Gillespie, Stephen H., Della Pasqua, Oscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744479/
https://www.ncbi.nlm.nih.gov/pubmed/31519935
http://dx.doi.org/10.1038/s41598-019-49556-5
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author Kloprogge, Frank
Hammond, Robert
Kipper, Karin
Gillespie, Stephen H.
Della Pasqua, Oscar
author_facet Kloprogge, Frank
Hammond, Robert
Kipper, Karin
Gillespie, Stephen H.
Della Pasqua, Oscar
author_sort Kloprogge, Frank
collection PubMed
description Here, we evaluate protocol requirements to mimic therapeutically relevant drug concentrations at the site of infection (i.e. lung lesion) in an in-vitro hollow fibre model of infection using pulmonary tuberculosis as a paradigm. Steady-state pharmacokinetic profiles in plasma, lung tissue and lung lesion homogenate were simulated for isoniazid, rifampicin and pyrazinamide and moxifloxacin. An R-shiny User Interface was developed to support conversion of in-vivo pharmacokinetic C(MAX), T(MAX) and T(1/2) estimates into pump settings. A monotherapy protocol mimicking isoniazid in lung lesion homogenate (isoniazid C(MAX) = 1,200 ng/ml, T(MAX) = 2.2 hr and T(1/2) = 4.7 hr), and two combination therapy protocols including drugs with similar (isoniazid and rifampicin (C(MAX) = 400 ng/ml)) and different half-lives (isoniazid and pyrazinamide (C(MAX) = 28,900 ng/ml and T(1/2) = 8.0 hr)) were implemented in a hollow-fiber system. Drug levels in the perfusate were analysed using ultra-high-performance liquid chromatographic-tandem mass spectrometric detection. Steady state pharmacokinetic profiles measured in the hollow fiber model were similar to the predicted in-vivo steady-state lung lesion homogenate pharmacokinetic profiles. The presented approach offers the possibility to use pharmacological data to study the effect of target tissue exposure for drug combinations. Integration with pharmacokinetics modelling principles through a web interface will provide access to a wider community interested in the evaluation of efficacy of anti-tubercular drugs.
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spelling pubmed-67444792019-09-27 Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection Kloprogge, Frank Hammond, Robert Kipper, Karin Gillespie, Stephen H. Della Pasqua, Oscar Sci Rep Article Here, we evaluate protocol requirements to mimic therapeutically relevant drug concentrations at the site of infection (i.e. lung lesion) in an in-vitro hollow fibre model of infection using pulmonary tuberculosis as a paradigm. Steady-state pharmacokinetic profiles in plasma, lung tissue and lung lesion homogenate were simulated for isoniazid, rifampicin and pyrazinamide and moxifloxacin. An R-shiny User Interface was developed to support conversion of in-vivo pharmacokinetic C(MAX), T(MAX) and T(1/2) estimates into pump settings. A monotherapy protocol mimicking isoniazid in lung lesion homogenate (isoniazid C(MAX) = 1,200 ng/ml, T(MAX) = 2.2 hr and T(1/2) = 4.7 hr), and two combination therapy protocols including drugs with similar (isoniazid and rifampicin (C(MAX) = 400 ng/ml)) and different half-lives (isoniazid and pyrazinamide (C(MAX) = 28,900 ng/ml and T(1/2) = 8.0 hr)) were implemented in a hollow-fiber system. Drug levels in the perfusate were analysed using ultra-high-performance liquid chromatographic-tandem mass spectrometric detection. Steady state pharmacokinetic profiles measured in the hollow fiber model were similar to the predicted in-vivo steady-state lung lesion homogenate pharmacokinetic profiles. The presented approach offers the possibility to use pharmacological data to study the effect of target tissue exposure for drug combinations. Integration with pharmacokinetics modelling principles through a web interface will provide access to a wider community interested in the evaluation of efficacy of anti-tubercular drugs. Nature Publishing Group UK 2019-09-13 /pmc/articles/PMC6744479/ /pubmed/31519935 http://dx.doi.org/10.1038/s41598-019-49556-5 Text en © The Author(s) 2019 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kloprogge, Frank
Hammond, Robert
Kipper, Karin
Gillespie, Stephen H.
Della Pasqua, Oscar
Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
title Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
title_full Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
title_fullStr Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
title_full_unstemmed Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
title_short Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
title_sort mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744479/
https://www.ncbi.nlm.nih.gov/pubmed/31519935
http://dx.doi.org/10.1038/s41598-019-49556-5
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