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长效替诺福韦艾拉酚胺经皮下植入剂给药用于 HIV 预防的基本问题。

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

机构信息

Department of Chemistry, Oak Crest Institute of Science, 128-132 W. Chestnut Ave., Monrovia, CA, USA.

Certara Integrated Drug Development, 2000 Peel Street, Suite 570, Montreal, QC, Canada.

出版信息

Sci Rep. 2022 May 17;12(1):8224. doi: 10.1038/s41598-022-11020-2.

DOI:10.1038/s41598-022-11020-2
PMID:35581262
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9114338/
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.

摘要

全球旨在预防易感染人群中人类免疫缺陷病毒 1 型（HIV-1）感染的努力似乎正在停滞不前，限制了我们控制疫情的能力。通过减少频繁给药相关的依从性负担，皮下植入长效、控释药物给药具有重要潜力。我们和其他人正在探索开发能够输送强效前药替诺福韦艾拉酚胺（TAF）的互补皮下植入技术。本报告利用几种小鼠模型解决了皮下长效 TAF 递药的临床前药理学中的知识空白。采用多室药代动力学（PK）模型解释了 TAF 植入给药期间的全身药物处置情况。成像质谱技术用于描绘植入部位周围局部组织中 TAF 及其主要五种代谢物的空间分布。人源化小鼠研究确定了预防阴道和直肠 HIV-1 感染的有效 TAF 剂量。我们的研究结果代表了开发用于 HIV-1 预防的安全有效的 TAF 植入物的重要一步。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/cdefd693d376/41598_2022_11020_Fig14_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/54c53f093ae4/41598_2022_11020_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/6659128fd826/41598_2022_11020_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/6608245d1a6d/41598_2022_11020_Fig4_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/d6efc2c7319d/41598_2022_11020_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/1baf81a0c380/41598_2022_11020_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/4cc93afc0345/41598_2022_11020_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/8e7696ac7b17/41598_2022_11020_Fig9a_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/430194ffae5c/41598_2022_11020_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/a6e0e4736730/41598_2022_11020_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/03b87039fd08/41598_2022_11020_Fig12_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/78ccbacb1c9f/41598_2022_11020_Fig13_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/cdefd693d376/41598_2022_11020_Fig14_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/92f626eba23f/41598_2022_11020_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/54c53f093ae4/41598_2022_11020_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/6659128fd826/41598_2022_11020_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/e76c2d7691b1/41598_2022_11020_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/6608245d1a6d/41598_2022_11020_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/839f0e019873/41598_2022_11020_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/d6efc2c7319d/41598_2022_11020_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/1baf81a0c380/41598_2022_11020_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/4cc93afc0345/41598_2022_11020_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/8e7696ac7b17/41598_2022_11020_Fig9a_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/430194ffae5c/41598_2022_11020_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/a6e0e4736730/41598_2022_11020_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/03b87039fd08/41598_2022_11020_Fig12_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/78ccbacb1c9f/41598_2022_11020_Fig13_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0958/9114338/cdefd693d376/41598_2022_11020_Fig14_HTML.jpg

相似文献

[1]
Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis.

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[2]
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[3]
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[5]
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[6]
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[5]
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[6]
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[7]
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[8]
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本文引用的文献

[1]
CAPRISA 018: a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release tenofovir alafenamide subdermal implant for HIV prevention in women.

BMJ Open. 2022-1-6

[2]
Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.

N Engl J Med. 2021-8-12

[3]
Tenofovir Alafenamide for HIV Prevention: Review of the Proceedings from the Gates Foundation Long-Acting TAF Product Development Meeting.

AIDS Res Hum Retroviruses. 2021-6

[4]
Characterization of Human Immunodeficiency Virus (HIV) Infection in Cisgender Men and Transgender Women Who Have Sex With Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083.

J Infect Dis. 2021-11-16

[5]
Cabotegravir-Rilpivirine: The First Complete Long-Acting Injectable Regimen for the Treatment of HIV-1 Infection.

Ann Pharmacother. 2021-11

[6]
Multispecies Evaluation of a Long-Acting Tenofovir Alafenamide Subdermal Implant for HIV Prophylaxis.

Front Pharmacol. 2020-11-25

[7]
Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP).

Pharmaceutics. 2020-11-5

[8]
Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant.

Pharmaceutics. 2020-10-17

[9]
Spatial Distribution Profiles of Emtricitabine, Tenofovir, Efavirenz, and Rilpivirine in Murine Tissues Following Dosing Correlate with Their Safety Profiles in Humans.

ACS Pharmacol Transl Sci. 2020-4-23

[10]
Highly synergistic drug combination prevents vaginal HIV infection in humanized mice.

Sci Rep. 2020-8-3

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