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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

Antimicrobial agents and chemotherapy, 2020-02, Vol.64 (3) [Periódico revisado por pares]

United States: American Society for Microbiology

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Título:
A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
Autor: 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
Assuntos: Adenine - adverse effects ; Adenine - analogs & derivatives ; Adenine - blood ; Adenine - pharmacokinetics ; Animals ; Anti-HIV Agents - adverse effects ; Anti-HIV Agents - blood ; Anti-HIV Agents - pharmacokinetics ; Antiviral Agents ; Delayed-Action Preparations ; Drug Implants - administration & dosage ; Female ; Fumarates - chemistry ; HIV Infections - prevention & control ; Humans ; Inflammation ; Macaca mulatta ; Male ; Necrosis - chemically induced ; Necrosis - pathology ; Polyurethanes - administration & dosage ; Rabbits ; Subcutaneous Tissue - surgery
É parte de: Antimicrobial agents and chemotherapy, 2020-02, Vol.64 (3)
Notas: Jonathan T. Su and Solange M. Simpson contributed equally to this work. Authorship order was decided in order of theoretical and conceptual contribution to the work.
Citation Su JT, Simpson SM, Sung S, Tfaily EB, Veazey R, Marzinke M, Qiu J, Watrous D, Widanapathirana L, Pearson E, Peet MM, Karunakaran D, Grasperge B, Dobek G, Cain CM, Hope T, Kiser PF. 2020. A subcutaneous implant of tenofovir alafenamide fumarate causes local inflammation and tissue necrosis in rabbits and macaques. Antimicrob Agents Chemother 64:e01893-19. https://doi.org/10.1128/AAC.01893-19.
Descrição: We describe the and 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 and 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 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.
Editor: United States: American Society for Microbiology
Idioma: Inglês

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

United States: American Society for Microbiology

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