Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir
| dc.contributor.advisor | Wiesner, Lubbe | |
| dc.contributor.advisor | Kellermann, Tracy | |
| dc.contributor.author | Kriegler Foster, Katie | |
| dc.date.accessioned | 2023-03-29T07:06:38Z | |
| dc.date.available | 2023-03-29T07:06:38Z | |
| dc.date.issued | 2022 | |
| dc.date.updated | 2023-03-15T13:43:00Z | |
| dc.description.abstract | 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. | |
| dc.identifier.apacitation | Kriegler Foster, K. (2022). <i>Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir</i>. (). ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/37541 | en_ZA |
| dc.identifier.chicagocitation | Kriegler Foster, Katie. <i>"Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir."</i> ., ,Faculty of Health Sciences ,Department of Medicine, 2022. http://hdl.handle.net/11427/37541 | en_ZA |
| dc.identifier.citation | Kriegler Foster, K. 2022. Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir. . ,Faculty of Health Sciences ,Department of Medicine. http://hdl.handle.net/11427/37541 | en_ZA |
| dc.identifier.ris | TY - Doctoral Thesis AU - Kriegler Foster, Katie AB - 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. DA - 2022_ DB - OpenUCT DP - University of Cape Town KW - Clinical Pharmacology LK - https://open.uct.ac.za PY - 2022 T1 - Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir TI - Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir UR - http://hdl.handle.net/11427/37541 ER - | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11427/37541 | |
| dc.identifier.vancouvercitation | Kriegler Foster K. Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir. []. ,Faculty of Health Sciences ,Department of Medicine, 2022 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/37541 | en_ZA |
| dc.language.rfc3066 | eng | |
| dc.publisher.department | Department of Medicine | |
| dc.publisher.faculty | Faculty of Health Sciences | |
| dc.subject | Clinical Pharmacology | |
| dc.title | Determination of total, unbound, and intracellular concentrations of the antiretroviral drugs Efavirenz, Lopinavir, and Ritonavir | |
| dc.type | Doctoral Thesis | |
| dc.type.qualificationlevel | Doctoral | |
| dc.type.qualificationlevel | PhD |