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Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs
Includes abstract.
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| Main Author: | |
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
Division of Clinical Pharmacology
2014
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| _version_ | 1867613242877018112 |
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| access_status_str | Open Access |
| author | Chigutsa, Emmanuel |
| author2 | McIlleron, Helen |
| author_browse | Chigutsa, Emmanuel McIlleron, Helen |
| author_facet | McIlleron, Helen Chigutsa, Emmanuel |
| author_sort | Chigutsa, Emmanuel |
| collection | Thesis |
| description | Includes abstract. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/3275 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:33:01.081Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2014 |
| publishDateRange | 2014 |
| publishDateSort | 2014 |
| 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:11427/3275 Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs Chigutsa, Emmanuel McIlleron, Helen Kirkpatrick, Carl Clinical Pharmacology Includes abstract. Includes bibliographical references. The pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in 78 patients with tuberculosis were described using non-linear mixed effects modeling. Pharmacodynamic data was comprised of weekly sputum liquid culture (using mycobacterial growth indicator tubes) time to detection results from 144 patients during the first 2 months of treatment. The effect of drug exposure on patient outcomes was investigated. To determine the adequacy of ofloxacin drug exposure, the probability of attaining the required area-under-the-curve to minimum inhibitory concentration ratio (AUC/MIC) of ofloxacin was determined in 65 patients on treatment for multidrug resistant tuberculosis. To improve efficiency in the clinical development of new drug regimens, clinical trial simulation was used to determine the optimal study design for a study investigating the efficacy of a new antitubercular drug regimen. The SLCO1B1 rs4149032 polymorphism existed at a high frequency of 0.70 in South Africans and resulted in a 28% decrease in bioavailability of rifampicin. The rifampicin peak concentration was a significant predictor of the 2 month treatment outcomes. A semimechanistic time to event model was developed to analyze days to positivity (time to detection) data. The model was comprised of a biexponential decay model describing bacillary decline in sputum from patients, followed by a logistic model with a lag time for growth of the mycobacteria in liquid culture. For the current 800 mg daily dose of ofloxacin, the probability of attaining an AUC/MIC target ratio of at least 100 was only 0.45. Based on clinical trial simulation, the optimum parallel study design was comprised of 125 study participants in each of 2 arms to achieve a study power of at least 80%. Increasing the study length beyond 42 days reduced study power perhaps due to increased amounts of censored data. Higher doses of rifampicin are required in the majority of South African patients with tuberculosis. A novel pharmacodynamic model of tuberculosis treatment is presented, which can be used for investigation of covariates such as drug exposure. Ofloxacin should be replaced with a more potent fluoroquinolone for treatment of multidrug resistant tuberculosis. Clinical trials should not be unduly long otherwise this may compromise study power. 2014-07-28T18:18:40Z 2014-07-28T18:18:40Z 2013 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/3275 eng application/pdf Division of Clinical Pharmacology Faculty of Health Sciences University of Cape Town |
| spellingShingle | Clinical Pharmacology Chigutsa, Emmanuel Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs |
| thesis_degree_str | Doctoral |
| title | Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs |
| title_full | Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs |
| title_fullStr | Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs |
| title_full_unstemmed | Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs |
| title_short | Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs |
| title_sort | population pharmacokinetics and pharmacokinetic pharmacodyamic modeling of antitubercular drugs |
| topic | Clinical Pharmacology |
| url | http://hdl.handle.net/11427/3275 |
| work_keys_str_mv | AT chigutsaemmanuel populationpharmacokineticsandpharmacokineticpharmacodyamicmodelingofantituberculardrugs |