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Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention

Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose...

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Autores principales: Jhunjhunwala, Kunal, Dobard, Charles W., Sharma, Sunita, Makarova, Natalia, Holder, Angela, Dinh, Chuong, Mitchell, James, Wang, Lin, Zhang, Junmei, Patel, Sravan Kumar, Heneine, Walid, Rohan, Lisa C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401959/
https://www.ncbi.nlm.nih.gov/pubmed/34452070
http://dx.doi.org/10.3390/pharmaceutics13081110
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author Jhunjhunwala, Kunal
Dobard, Charles W.
Sharma, Sunita
Makarova, Natalia
Holder, Angela
Dinh, Chuong
Mitchell, James
Wang, Lin
Zhang, Junmei
Patel, Sravan Kumar
Heneine, Walid
Rohan, Lisa C.
author_facet Jhunjhunwala, Kunal
Dobard, Charles W.
Sharma, Sunita
Makarova, Natalia
Holder, Angela
Dinh, Chuong
Mitchell, James
Wang, Lin
Zhang, Junmei
Patel, Sravan Kumar
Heneine, Walid
Rohan, Lisa C.
author_sort Jhunjhunwala, Kunal
collection PubMed
description Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose combination of tenofovir (TFV) and elvitegravir (EVG) (40 mg each) was co-formulated in six different suppository bases (three fat- and three water-soluble). Fat-soluble witepsol H15 and water-soluble polyethylene glycol (PEG) based suppositories demonstrated favorable in vitro release and were advanced to assess in vivo pharmacokinetics following rectal administration in macaques. In vivo drug release profiles were similar for both suppository bases. Median concentrations of TFV and EVG detected in rectal fluids at 2 h were 1- and 2-logs higher than the in vitro IC50, respectively; TFV-diphosphate levels in rectal tissues met or exceeded those associated with high efficacy against rectal simian HIV (SHIV) exposure in macaques. Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development.
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spelling pubmed-84019592021-08-29 Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention Jhunjhunwala, Kunal Dobard, Charles W. Sharma, Sunita Makarova, Natalia Holder, Angela Dinh, Chuong Mitchell, James Wang, Lin Zhang, Junmei Patel, Sravan Kumar Heneine, Walid Rohan, Lisa C. Pharmaceutics Article Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose combination of tenofovir (TFV) and elvitegravir (EVG) (40 mg each) was co-formulated in six different suppository bases (three fat- and three water-soluble). Fat-soluble witepsol H15 and water-soluble polyethylene glycol (PEG) based suppositories demonstrated favorable in vitro release and were advanced to assess in vivo pharmacokinetics following rectal administration in macaques. In vivo drug release profiles were similar for both suppository bases. Median concentrations of TFV and EVG detected in rectal fluids at 2 h were 1- and 2-logs higher than the in vitro IC50, respectively; TFV-diphosphate levels in rectal tissues met or exceeded those associated with high efficacy against rectal simian HIV (SHIV) exposure in macaques. Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development. MDPI 2021-07-21 /pmc/articles/PMC8401959/ /pubmed/34452070 http://dx.doi.org/10.3390/pharmaceutics13081110 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jhunjhunwala, Kunal
Dobard, Charles W.
Sharma, Sunita
Makarova, Natalia
Holder, Angela
Dinh, Chuong
Mitchell, James
Wang, Lin
Zhang, Junmei
Patel, Sravan Kumar
Heneine, Walid
Rohan, Lisa C.
Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention
title Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention
title_full Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention
title_fullStr Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention
title_full_unstemmed Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention
title_short Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention
title_sort development, characterization and in vivo pharmacokinetic assessment of rectal suppositories containing combination antiretroviral drugs for hiv prevention
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401959/
https://www.ncbi.nlm.nih.gov/pubmed/34452070
http://dx.doi.org/10.3390/pharmaceutics13081110
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