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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Veröffentlicht in:Scientific reports Jg. 12; H. 1; S. 8224 - 25
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 17.05.2022
Nature Publishing Group
Nature Portfolio
Schlagworte:
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
Online-Zugang:Volltext
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Zusammenfassung: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-11020-2