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Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling

This pharmacokinetic sub-study was nested within the phase-III OFLOTUB study investigating the shortening of tuberculosis treatment. A total of 343 adults enrolled in Benin, Guinea, Senegal, and South Africa were randomized to receive rifampicin, isoniazid, pyrazinamide, and ethambutol in the standa...

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Main Author: Smythe, Wynand Anton
Other Authors: McIlleron, Helen
Format: Thesis
Language:English
Published: Division of Clinical Pharmacology 2016
Subjects:
Clinical Pharmacology
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access_status_str Open Access
author Smythe, Wynand Anton
author2 McIlleron, Helen
author_browse McIlleron, Helen
Smythe, Wynand Anton
author_facet McIlleron, Helen
Smythe, Wynand Anton
author_sort Smythe, Wynand Anton
collection Thesis
description This pharmacokinetic sub-study was nested within the phase-III OFLOTUB study investigating the shortening of tuberculosis treatment. A total of 343 adults enrolled in Benin, Guinea, Senegal, and South Africa were randomized to receive rifampicin, isoniazid, pyrazinamide, and ethambutol in the standard 6-month control regimen or the 4-month test regimen where gatifloxacin replaced ethambutol. The pharmacokinetics of all drugs was described at first dose and steady-state using nonlinear mixed-effects modelling, and individual exposures were summarised as area under the concentration-time curve (AUC0-24) and peak concentration. Autoinduction of rifampicin metabolism was characterized with a semi-mechanistic enzyme turn-over model. Gatifloxacin dose was evaluated using Monte Carlo simulations. Lastly, Classification & Regression Tree (CART) analysis techniques were used to identify factors predictive of 2-month culture conversion or 24-month long-term composite outcome. Consistent with literature findings, approximately 73.0, 43.0, 0.3, 6.0 and 0.0% of patients failed to achieve previously reported target concentrations for rifampicin, isoniazid, pyrazinamide, ethambutol, and gatifloxacin, respectively.
format Thesis
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institution University of Cape Town (South Africa)
language eng
last_indexed 2026-06-10T12:43:17.330Z
license_str Not specified — see source repository
provenance_str_mv Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository
publishDate 2016
publishDateRange 2016
publishDateSort 2016
publisher Division of Clinical Pharmacology
publisherStr Division of Clinical Pharmacology
record_format dspace
source_str UCTD — University of Cape Town Open Access Repository
spelling oai:open.uct.ac.za:11427/20425 Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling Smythe, Wynand Anton McIlleron, Helen Denti, Paolo Clinical Pharmacology This pharmacokinetic sub-study was nested within the phase-III OFLOTUB study investigating the shortening of tuberculosis treatment. A total of 343 adults enrolled in Benin, Guinea, Senegal, and South Africa were randomized to receive rifampicin, isoniazid, pyrazinamide, and ethambutol in the standard 6-month control regimen or the 4-month test regimen where gatifloxacin replaced ethambutol. The pharmacokinetics of all drugs was described at first dose and steady-state using nonlinear mixed-effects modelling, and individual exposures were summarised as area under the concentration-time curve (AUC0-24) and peak concentration. Autoinduction of rifampicin metabolism was characterized with a semi-mechanistic enzyme turn-over model. Gatifloxacin dose was evaluated using Monte Carlo simulations. Lastly, Classification & Regression Tree (CART) analysis techniques were used to identify factors predictive of 2-month culture conversion or 24-month long-term composite outcome. Consistent with literature findings, approximately 73.0, 43.0, 0.3, 6.0 and 0.0% of patients failed to achieve previously reported target concentrations for rifampicin, isoniazid, pyrazinamide, ethambutol, and gatifloxacin, respectively. 2016-07-18T12:51:31Z 2016-07-18T12:51:31Z 2016 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/20425 eng application/pdf Division of Clinical Pharmacology Faculty of Health Sciences University of Cape Town
spellingShingle Clinical Pharmacology
Smythe, Wynand Anton
Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
thesis_degree_str Doctoral
title Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
title_full Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
title_fullStr Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
title_full_unstemmed Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
title_short Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
title_sort characterizing population pharmacokinetic pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
topic Clinical Pharmacology
url http://hdl.handle.net/11427/20425
work_keys_str_mv AT smythewynandanton characterizingpopulationpharmacokineticpharmacodynamicrelationshipsinpulmonarytuberculosisinfectedadultsusingnonlinearmixedeffectsmodelling

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