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

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dc.contributor.advisorMcIlleron, Helenen_ZA
dc.contributor.advisorDenti, Paoloen_ZA
dc.contributor.authorSmythe, Wynand Antonen_ZA
dc.date.accessioned2016-07-18T12:51:31Z
dc.date.available2016-07-18T12:51:31Z
dc.date.issued2016en_ZA
dc.description.abstractThis 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.en_ZA
dc.identifier.apacitationSmythe, W. A. (2016). <i>Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology. Retrieved from http://hdl.handle.net/11427/20425en_ZA
dc.identifier.chicagocitationSmythe, Wynand Anton. <i>"Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology, 2016. http://hdl.handle.net/11427/20425en_ZA
dc.identifier.citationSmythe, W. 2016. Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Smythe, Wynand Anton AB - 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. DA - 2016 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2016 T1 - Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling TI - Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling UR - http://hdl.handle.net/11427/20425 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/20425
dc.identifier.vancouvercitationSmythe WA. Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology, 2016 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/20425en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherClinical Pharmacologyen_ZA
dc.titleCharacterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modellingen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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