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A model-based analysis identifies differences in phenotypic resistance between in vitro and in vivo: implications for translational medicine within tuberculosis.

Clewe, O; Faraj, A; Hu, Y; Coates, ARM; Simonsson, USH (2020) A model-based analysis identifies differences in phenotypic resistance between in vitro and in vivo: implications for translational medicine within tuberculosis. J Pharmacokinet Pharmacodyn, 47 (5). pp. 421-430. ISSN 1573-8744 https://doi.org/10.1007/s10928-020-09694-0
SGUL Authors: Coates, Anthony Robert Milnes Hu, Yanmin

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Abstract

Proper characterization of drug effects on Mycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure-response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of in vitro and in vivo phenotypic resistance i.e. persisters, using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated based on bacterial cultures grown with and without drug exposure using CFU alone or CFU plus MPN data. Phenotypic resistance and total bacterial number in in vitro natural growth observations, i.e. without drug, was well predicted by the MTP model using only CFU data. Capturing the murine in vivo total bacterial number and persisters during natural growth did however require re-estimation of model parameter using both the CFU and MPN observations implying that the ratio of persisters to total bacterial burden is different in vitro compared to murine in vivo. The evaluation of the in vitro rifampicin drug effect revealed that higher resolution in the persister drug effect was seen using CFU and MPN compared to CFU alone although drug effects on the other bacterial populations were well predicted using only CFU data. The ratio of persistent bacteria to total bacteria was predicted to be different between in vitro and murine in vivo. This difference could have implications for subsequent translational efforts in tuberculosis drug development.

Item Type: Article
Additional Information: © The Author(s) 2020 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 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/.
Keywords: Pharmacodynamics, Phenotypic resistance, Translational modelling, Tuberculosis, Pharmacology & Pharmacy, 1115 Pharmacology and Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: J Pharmacokinet Pharmacodyn
ISSN: 1573-8744
Language: eng
Dates:
DateEvent
October 2020Published
1 June 2020Published Online
28 May 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
521-2011-3442Vetenskapsrådet (SE)UNSPECIFIED
n115337Innovative Medicines Initiative JointUNSPECIFIED
PubMed ID: 32488575
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112020
Publisher's version: https://doi.org/10.1007/s10928-020-09694-0

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