Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis

Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the co...

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Published in:Scientific reports Vol. 12; no. 1; pp. 8224 - 25
Main Authors: Gunawardana, Manjula, Remedios-Chan, Mariana, Sanchez, Debbie, Webster, Simon, Castonguay, Amalia E., Webster, Paul, Buser, Christopher, Moss, John A., Trinh, MyMy, Beliveau, Martin, Hendrix, Craig W., Marzinke, Mark A., Tuck, Michael, Caprioli, Richard M., Reyzer, Michelle L., Kuo, Joseph, Gallay, Philippe A., Baum, Marc M.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 17.05.2022
Nature Publishing Group
Nature Portfolio
Subjects:
631/154/152
692/308/153
Adenine
Alanine - therapeutic use
Animal models
Animals
Anti-HIV Agents
Antiretroviral drugs
At risk populations
Dosage
Drug dosages
Female
HIV
HIV Infections - drug therapy
HIV Infections - prevention & control
Human immunodeficiency virus
Humanities and Social Sciences
Mass spectrometry
Mass spectroscopy
Metabolites
Mice
multidisciplinary
Pharmacokinetics
Pharmacology
Prophylaxis
Science
Science (multidisciplinary)
Spatial distribution
Tenofovir
Tenofovir - analogs & derivatives
Tenofovir - therapeutic use
Transplants & implants
ISSN:2045-2322, 2045-2322
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Abstract Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.
AbstractList Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.
Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.
Abstract Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.
ArticleNumber 8224
Author Gallay, Philippe A.
Tuck, Michael
Sanchez, Debbie
Gunawardana, Manjula
Trinh, MyMy
Webster, Simon
Castonguay, Amalia E.
Beliveau, Martin
Hendrix, Craig W.
Caprioli, Richard M.
Reyzer, Michelle L.
Baum, Marc M.
Kuo, Joseph
Moss, John A.
Webster, Paul
Remedios-Chan, Mariana
Marzinke, Mark A.
Buser, Christopher
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  organization: Department of Chemistry, Oak Crest Institute of Science
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  surname: Remedios-Chan
  fullname: Remedios-Chan, Mariana
  organization: Department of Chemistry, Oak Crest Institute of Science
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  organization: Department of Chemistry, Oak Crest Institute of Science
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  organization: Certara Integrated Drug Development
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  givenname: Craig W.
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  organization: Department of Medicine, Johns Hopkins University
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  givenname: Mark A.
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  givenname: Michael
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  organization: Department of Biochemistry, Vanderbilt University
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  givenname: Richard M.
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  organization: Department of Biochemistry, Vanderbilt University
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  surname: Baum
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  email: m.baum@oak-crest.org
  organization: Department of Chemistry, Oak Crest Institute of Science
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Snippet Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our...
Abstract Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting...
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crossref
springer
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StartPage 8224
SubjectTerms 631/154/152
692/308/153
Adenine
Alanine - therapeutic use
Animal models
Animals
Anti-HIV Agents
Antiretroviral drugs
At risk populations
Dosage
Drug dosages
Female
HIV
HIV Infections - drug therapy
HIV Infections - prevention & control
Human immunodeficiency virus
Humanities and Social Sciences
Mass spectrometry
Mass spectroscopy
Metabolites
Mice
multidisciplinary
Pharmacokinetics
Pharmacology
Prophylaxis
Science
Science (multidisciplinary)
Spatial distribution
Tenofovir
Tenofovir - analogs & derivatives
Tenofovir - therapeutic use
Transplants & implants
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Title Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis
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