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Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads
Preclinical pharmacokinetics relies on efficient and accurate screening to select clinical candidates from early leads. Poor pharmacokinetic interpretation can disadvantage drug discovery by promoting inadequate compounds and expelling potential drug candidates. Objectives of this project included p...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2019
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| _version_ | 1867613255575273472 |
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| access_status_str | Open Access |
| author | Strydom, Natasha |
| author2 | Chibale, Kelly |
| author_browse | Chibale, Kelly Strydom, Natasha |
| author_facet | Chibale, Kelly Strydom, Natasha |
| author_sort | Strydom, Natasha |
| collection | Thesis |
| description | Preclinical pharmacokinetics relies on efficient and accurate screening to select clinical candidates from early leads. Poor pharmacokinetic interpretation can disadvantage drug discovery by promoting inadequate compounds and expelling potential drug candidates. Objectives of this project included pharmacokinetic evaluation of antimalarial and anti-tuberculosis lead compounds with techniques aimed at improving preclinical pharmacokinetic outcomes. This included mechanistic pharmacokinetic approaches such as non-linear mixed effects (NLME) modelling in comparison with traditional non-compartmental analysis. Where appropriate, pharmacokinetic methods were expanded to include organ distribution and capsule dosing in mice to bridge our techniques from discovery to early development. Three benzoxazole amodiaquine analogues possessing equipotent in vitro antiplasmodial activity and showed diverse in vivo efficacy in a malaria mouse model. Evaluation of their respective pharmacokinetics in mice showed their in vivo exposures could translate to in vivo efficacy. Retrospective PK/PD simulations point to a time above IC50 drive in efficacy. Pharmacokinetic evaluation of an aminopyridine antimalarial compound in its cyclodextrin inclusion complex revealed a pH dependent increase in solubility that reduced variance, likely due to favoured intestinal absorption. Investigation of two novel fusidic acid C-3 ester prodrugs aimed at repositioning fusidic acid for tuberculosis, showed high concentrations of the rodent specific 3-epifusidic acid metabolite that greatly reduced exposure of fusidic acid in mice. Further organ distribution studies showed a prodrug strategy is still viable for repositioning fusidic acid for tuberculosis, but that rodent models are inappropriate for further evaluation. NLME modelling successfully provided unique mechanistic and mathematical insight of pharmacokinetic profiles of new leads. The level of interpretation on pharmacology parameters improved and aided in understanding why drug leads are likely to fail or succeed, assisting future compound optimisation. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/29467 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:33:13.838Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| publisher | Department of Chemistry |
| publisherStr | Department of Chemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/29467 Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads Strydom, Natasha Chibale, Kelly Wiesner, Lubbe Chemistry Preclinical pharmacokinetics relies on efficient and accurate screening to select clinical candidates from early leads. Poor pharmacokinetic interpretation can disadvantage drug discovery by promoting inadequate compounds and expelling potential drug candidates. Objectives of this project included pharmacokinetic evaluation of antimalarial and anti-tuberculosis lead compounds with techniques aimed at improving preclinical pharmacokinetic outcomes. This included mechanistic pharmacokinetic approaches such as non-linear mixed effects (NLME) modelling in comparison with traditional non-compartmental analysis. Where appropriate, pharmacokinetic methods were expanded to include organ distribution and capsule dosing in mice to bridge our techniques from discovery to early development. Three benzoxazole amodiaquine analogues possessing equipotent in vitro antiplasmodial activity and showed diverse in vivo efficacy in a malaria mouse model. Evaluation of their respective pharmacokinetics in mice showed their in vivo exposures could translate to in vivo efficacy. Retrospective PK/PD simulations point to a time above IC50 drive in efficacy. Pharmacokinetic evaluation of an aminopyridine antimalarial compound in its cyclodextrin inclusion complex revealed a pH dependent increase in solubility that reduced variance, likely due to favoured intestinal absorption. Investigation of two novel fusidic acid C-3 ester prodrugs aimed at repositioning fusidic acid for tuberculosis, showed high concentrations of the rodent specific 3-epifusidic acid metabolite that greatly reduced exposure of fusidic acid in mice. Further organ distribution studies showed a prodrug strategy is still viable for repositioning fusidic acid for tuberculosis, but that rodent models are inappropriate for further evaluation. NLME modelling successfully provided unique mechanistic and mathematical insight of pharmacokinetic profiles of new leads. The level of interpretation on pharmacology parameters improved and aided in understanding why drug leads are likely to fail or succeed, assisting future compound optimisation. 2019-02-11T13:12:16Z 2019-02-11T13:12:16Z 2018 2019-02-11T11:43:27Z Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/29467 eng application/pdf Department of Chemistry Faculty of Science University of Cape Town |
| spellingShingle | Chemistry Strydom, Natasha Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads |
| thesis_degree_str | Doctoral |
| title | Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads |
| title_full | Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads |
| title_fullStr | Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads |
| title_full_unstemmed | Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads |
| title_short | Preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads |
| title_sort | preclinical pharmacokinetic evaluation of novel antimalarial and antituberculosis drug leads |
| topic | Chemistry |
| url | http://hdl.handle.net/11427/29467 |
| work_keys_str_mv | AT strydomnatasha preclinicalpharmacokineticevaluationofnovelantimalarialandantituberculosisdrugleads |