Cargando…

Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB

BACKGROUND: Bedaquiline has been shown to reduce time to sputum culture conversion (SCC) and increase cure rates in patients with drug-resistant TB, but the influence of drug exposure remains uncharacterized. OBJECTIVES: To investigate whether an exposure–response relationship could be characterized...

Descripción completa

Detalles Bibliográficos
Autores principales: Svensson, Elin M, Karlsson, Mats O
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890768/
https://www.ncbi.nlm.nih.gov/pubmed/28961790
http://dx.doi.org/10.1093/jac/dkx317
_version_ 1783312916258226176
author Svensson, Elin M
Karlsson, Mats O
author_facet Svensson, Elin M
Karlsson, Mats O
author_sort Svensson, Elin M
collection PubMed
description BACKGROUND: Bedaquiline has been shown to reduce time to sputum culture conversion (SCC) and increase cure rates in patients with drug-resistant TB, but the influence of drug exposure remains uncharacterized. OBJECTIVES: To investigate whether an exposure–response relationship could be characterized by making better use of the existing information on pharmacokinetics and longitudinal measurements of mycobacterial load. METHODS: Quantitative culture data in the form of time to positivity (TTP) in mycobacterial growth indicator tubes obtained from a randomized placebo-controlled Phase IIb registration trial were examined using non-linear mixed-effects methodology. The link to individual bedaquiline exposures and other patient characteristics was evaluated. RESULTS: The developed model included three simultaneously fitted components: a longitudinal representation of mycobacterial load in patients, a probabilistic component for bacterial presence in sputum samples, and a time-to-event model for TTP. Data were described adequately, and time to SCC was well predicted. Individual bedaquiline exposure was found to significantly affect the decline in mycobacterial load. Consequently, the proportion of patients without SCC at week 20 is expected to decrease from 25% (95% CI 20%–31%) without bedaquiline to 17% (95% CI 13%–21%), 12% (95% CI 8%–16%) and 7% (95% CI 4%–11%), respectively, with half the median, median and double the median bedaquiline exposure observed in patients with standard dosing. Baseline bacterial load and level of drug resistance were other important predictors. CONCLUSIONS: To our knowledge, this is the first successful description of bedaquiline’s exposure–response relationship and may be used when considering dose optimization. Characterization of this relationship was possible by integrating quantitative information in existing clinical data using novel models.
format Online
Article
Text
id pubmed-5890768
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-58907682018-04-12 Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB Svensson, Elin M Karlsson, Mats O J Antimicrob Chemother Original Research BACKGROUND: Bedaquiline has been shown to reduce time to sputum culture conversion (SCC) and increase cure rates in patients with drug-resistant TB, but the influence of drug exposure remains uncharacterized. OBJECTIVES: To investigate whether an exposure–response relationship could be characterized by making better use of the existing information on pharmacokinetics and longitudinal measurements of mycobacterial load. METHODS: Quantitative culture data in the form of time to positivity (TTP) in mycobacterial growth indicator tubes obtained from a randomized placebo-controlled Phase IIb registration trial were examined using non-linear mixed-effects methodology. The link to individual bedaquiline exposures and other patient characteristics was evaluated. RESULTS: The developed model included three simultaneously fitted components: a longitudinal representation of mycobacterial load in patients, a probabilistic component for bacterial presence in sputum samples, and a time-to-event model for TTP. Data were described adequately, and time to SCC was well predicted. Individual bedaquiline exposure was found to significantly affect the decline in mycobacterial load. Consequently, the proportion of patients without SCC at week 20 is expected to decrease from 25% (95% CI 20%–31%) without bedaquiline to 17% (95% CI 13%–21%), 12% (95% CI 8%–16%) and 7% (95% CI 4%–11%), respectively, with half the median, median and double the median bedaquiline exposure observed in patients with standard dosing. Baseline bacterial load and level of drug resistance were other important predictors. CONCLUSIONS: To our knowledge, this is the first successful description of bedaquiline’s exposure–response relationship and may be used when considering dose optimization. Characterization of this relationship was possible by integrating quantitative information in existing clinical data using novel models. Oxford University Press 2017-12 2017-09-13 /pmc/articles/PMC5890768/ /pubmed/28961790 http://dx.doi.org/10.1093/jac/dkx317 Text en © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Research
Svensson, Elin M
Karlsson, Mats O
Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB
title Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB
title_full Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB
title_fullStr Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB
title_full_unstemmed Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB
title_short Modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant TB
title_sort modelling of mycobacterial load reveals bedaquiline’s exposure–response relationship in patients with drug-resistant tb
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890768/
https://www.ncbi.nlm.nih.gov/pubmed/28961790
http://dx.doi.org/10.1093/jac/dkx317
work_keys_str_mv AT svenssonelinm modellingofmycobacterialloadrevealsbedaquilinesexposureresponserelationshipinpatientswithdrugresistanttb
AT karlssonmatso modellingofmycobacterialloadrevealsbedaquilinesexposureresponserelationshipinpatientswithdrugresistanttb