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A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluat...

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Autores principales: Su, Jonathan T., Simpson, Solange M., Sung, Samuel, Tfaily, Ewa Bryndza, Veazey, Ronald, Marzinke, Mark, Qiu, Jiang, Watrous, David, Widanapathirana, Lakmini, Pearson, Elizabeth, Peet, M. Melissa, Karunakaran, Dipu, Grasperge, Brooke, Dobek, Georgina, Cain, Charlette M., Hope, Thomas, Kiser, Patrick F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038301/
https://www.ncbi.nlm.nih.gov/pubmed/31871073
http://dx.doi.org/10.1128/AAC.01893-19
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author Su, Jonathan T.
Simpson, Solange M.
Sung, Samuel
Tfaily, Ewa Bryndza
Veazey, Ronald
Marzinke, Mark
Qiu, Jiang
Watrous, David
Widanapathirana, Lakmini
Pearson, Elizabeth
Peet, M. Melissa
Karunakaran, Dipu
Grasperge, Brooke
Dobek, Georgina
Cain, Charlette M.
Hope, Thomas
Kiser, Patrick F.
author_facet Su, Jonathan T.
Simpson, Solange M.
Sung, Samuel
Tfaily, Ewa Bryndza
Veazey, Ronald
Marzinke, Mark
Qiu, Jiang
Watrous, David
Widanapathirana, Lakmini
Pearson, Elizabeth
Peet, M. Melissa
Karunakaran, Dipu
Grasperge, Brooke
Dobek, Georgina
Cain, Charlette M.
Hope, Thomas
Kiser, Patrick F.
author_sort Su, Jonathan T.
collection PubMed
description We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 10(6) rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.
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spelling pubmed-70383012020-03-06 A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques Su, Jonathan T. Simpson, Solange M. Sung, Samuel Tfaily, Ewa Bryndza Veazey, Ronald Marzinke, Mark Qiu, Jiang Watrous, David Widanapathirana, Lakmini Pearson, Elizabeth Peet, M. Melissa Karunakaran, Dipu Grasperge, Brooke Dobek, Georgina Cain, Charlette M. Hope, Thomas Kiser, Patrick F. Antimicrob Agents Chemother Antiviral Agents We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 10(6) rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface. American Society for Microbiology 2020-02-21 /pmc/articles/PMC7038301/ /pubmed/31871073 http://dx.doi.org/10.1128/AAC.01893-19 Text en Copyright © 2020 Su et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Antiviral Agents
Su, Jonathan T.
Simpson, Solange M.
Sung, Samuel
Tfaily, Ewa Bryndza
Veazey, Ronald
Marzinke, Mark
Qiu, Jiang
Watrous, David
Widanapathirana, Lakmini
Pearson, Elizabeth
Peet, M. Melissa
Karunakaran, Dipu
Grasperge, Brooke
Dobek, Georgina
Cain, Charlette M.
Hope, Thomas
Kiser, Patrick F.
A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
title A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
title_full A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
title_fullStr A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
title_full_unstemmed A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
title_short A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
title_sort subcutaneous implant of tenofovir alafenamide fumarate causes local inflammation and tissue necrosis in rabbits and macaques
topic Antiviral Agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038301/
https://www.ncbi.nlm.nih.gov/pubmed/31871073
http://dx.doi.org/10.1128/AAC.01893-19
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