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Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir
Efavirenz, lopinavir, and ritonavir are antiretroviral drugs used for the treatment of HIV in South Africa. Plasma concentrations of these drugs are routinely monitored to ensure efficacy, minimise adverse effects, and adjust dosing. However, variability exists in patient treatment response and tole...
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| Format: | Thesis |
| Language: | English |
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Department of Medicine
2023
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| _version_ | 1867613305683574784 |
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| access_status_str | Open Access |
| author | Kriegler Foster, Katie |
| author2 | Wiesner, Lubbe |
| author_browse | Kriegler Foster, Katie Wiesner, Lubbe |
| author_facet | Wiesner, Lubbe Kriegler Foster, Katie |
| author_sort | Kriegler Foster, Katie |
| collection | Thesis |
| description | Efavirenz, lopinavir, and ritonavir are antiretroviral drugs used for the treatment of HIV in South Africa. Plasma concentrations of these drugs are routinely monitored to ensure efficacy, minimise adverse effects, and adjust dosing. However, variability exists in patient treatment response and tolerability, which cannot always be explained by the therapeutic drug monitoring results. This may be due to variability in the amount of drug reaching the target site within the HIV-infected cells. Therefore, intracellular drug concentrations could provide a more accurate depiction of drug exposure. An alternative to intracellular drug concentrations could be the quantitation of drug not bound to plasma proteins as this is the portion able to diffuse into tissues and cells to exert a therapeutic effect. A method is described for the quantification of intracellular efavirenz, lopinavir, and ritonavir from one million human peripheral blood mononuclear cells. In addition, the quantification of unbound efavirenz, lopinavir, and ritonavir from human plasma using ultracentrifugation is demonstrated, including a novel surrogate matrix. The two methods were validated according to the United States Food and Drug Administration and European Medicines Agency guidelines and proven to be accurate, precise, and reproducible. Both methods were submitted to the United States National Institute of Allergy and Infectious Diseases' Clinical Pharmacology Quality Assurance group for review and have been approved for use on clinical samples. A proof-of-concept correlation study of intracellular, unbound, and total drug concentrations is described using blood samples from six HIV-positive patients. A further patient unresponsive to lopinavir treatment, despite total plasma concentrations within the normal therapeutic range, was also evaluated. Paired plasma and cell samples indicated that the drug reached the target site within the cells, eliminating a possible cause of treatment failure. These findings show the utility and validity of these methods in a clinical setting to provide an overall view of treatment response and support their novel application in individualised patient care in South Africa. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/37541 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:34:00.978Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Department of Medicine |
| publisherStr | Department of Medicine |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/37541 Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir Kriegler Foster, Katie Wiesner, Lubbe Kellermann, Tracy Clinical Pharmacology Efavirenz, lopinavir, and ritonavir are antiretroviral drugs used for the treatment of HIV in South Africa. Plasma concentrations of these drugs are routinely monitored to ensure efficacy, minimise adverse effects, and adjust dosing. However, variability exists in patient treatment response and tolerability, which cannot always be explained by the therapeutic drug monitoring results. This may be due to variability in the amount of drug reaching the target site within the HIV-infected cells. Therefore, intracellular drug concentrations could provide a more accurate depiction of drug exposure. An alternative to intracellular drug concentrations could be the quantitation of drug not bound to plasma proteins as this is the portion able to diffuse into tissues and cells to exert a therapeutic effect. A method is described for the quantification of intracellular efavirenz, lopinavir, and ritonavir from one million human peripheral blood mononuclear cells. In addition, the quantification of unbound efavirenz, lopinavir, and ritonavir from human plasma using ultracentrifugation is demonstrated, including a novel surrogate matrix. The two methods were validated according to the United States Food and Drug Administration and European Medicines Agency guidelines and proven to be accurate, precise, and reproducible. Both methods were submitted to the United States National Institute of Allergy and Infectious Diseases' Clinical Pharmacology Quality Assurance group for review and have been approved for use on clinical samples. A proof-of-concept correlation study of intracellular, unbound, and total drug concentrations is described using blood samples from six HIV-positive patients. A further patient unresponsive to lopinavir treatment, despite total plasma concentrations within the normal therapeutic range, was also evaluated. Paired plasma and cell samples indicated that the drug reached the target site within the cells, eliminating a possible cause of treatment failure. These findings show the utility and validity of these methods in a clinical setting to provide an overall view of treatment response and support their novel application in individualised patient care in South Africa. 2023-03-29T07:06:38Z 2023-03-29T07:06:38Z 2022 2023-03-15T13:43:00Z Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/37541 eng application/pdf Department of Medicine Faculty of Health Sciences |
| spellingShingle | Clinical Pharmacology Kriegler Foster, Katie Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir |
| thesis_degree_str | Doctoral |
| title | Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir |
| title_full | Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir |
| title_fullStr | Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir |
| title_full_unstemmed | Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir |
| title_short | Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir |
| title_sort | determination of total unbound and intracellular concentrations of the antiretroviral drugs efavirenz lopinavir and ritonavir |
| topic | Clinical Pharmacology |
| url | http://hdl.handle.net/11427/37541 |
| work_keys_str_mv | AT krieglerfosterkatie determinationoftotalunboundandintracellularconcentrationsoftheantiretroviraldrugsefavirenzlopinavirandritonavir |