Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration

Abstract Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To a...

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Autores principales:	Ghaith Aljayyoussi, Victoria A. Jenkins, Raman Sharma, Alison Ardrey, Samantha Donnellan, Stephen A. Ward, Giancarlo A. Biagini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eeb7497b0cef443d825c81af2749fe7b
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spelling	oai:doaj.org-article:eeb7497b0cef443d825c81af2749fe7b2021-12-02T16:06:02ZPharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration10.1038/s41598-017-00529-62045-2322https://doaj.org/article/eeb7497b0cef443d825c81af2749fe7b2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00529-6https://doaj.org/toc/2045-2322Abstract Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.Ghaith AljayyoussiVictoria A. JenkinsRaman SharmaAlison ArdreySamantha DonnellanStephen A. WardGiancarlo A. BiaginiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ghaith Aljayyoussi Victoria A. Jenkins Raman Sharma Alison Ardrey Samantha Donnellan Stephen A. Ward Giancarlo A. Biagini Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
description	Abstract Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.
format	article
author	Ghaith Aljayyoussi Victoria A. Jenkins Raman Sharma Alison Ardrey Samantha Donnellan Stephen A. Ward Giancarlo A. Biagini
author_facet	Ghaith Aljayyoussi Victoria A. Jenkins Raman Sharma Alison Ardrey Samantha Donnellan Stephen A. Ward Giancarlo A. Biagini
author_sort	Ghaith Aljayyoussi
title	Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
title_short	Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
title_full	Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
title_fullStr	Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
title_full_unstemmed	Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
title_sort	pharmacokinetic-pharmacodynamic modelling of intracellular mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/eeb7497b0cef443d825c81af2749fe7b
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Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration

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