Novel Perspectives on the Design and Development of a Long-Acting Subcutaneous Raltegravir Injection for Treatment of HIV-In Vitro and In Vivo Evaluation
Antiretrovirals (ARVs) are a highly effective therapy for treatment and prevention of HIV infection, when administered as prescribed. However, adherence to lifelong ARV regimens poses a considerable challenge and places HIV patients at risk. Long-acting ARV injections may improve patient adherence a...
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| Main Authors: | , , , |
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| Format: | Book |
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MDPI AG,
2023-05-01T00:00:00Z.
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| Summary: | Antiretrovirals (ARVs) are a highly effective therapy for treatment and prevention of HIV infection, when administered as prescribed. However, adherence to lifelong ARV regimens poses a considerable challenge and places HIV patients at risk. Long-acting ARV injections may improve patient adherence as well as maintaining long-term continuous drug exposure, resulting in improved pharmacodynamics. In the present work, we explored the aminoalkoxycarbonyloxymethyl (amino-AOCOM) ether prodrug concept as a potential approach to long-acting ARV injections. As a proof of concept, we synthesised model compounds containing the 4-carboxy-2-methyl Tokyo Green (CTG) fluorophore and assessed their stability under pH and temperature conditions that mimic those found in the subcutaneous (SC) tissue. Among them, probe <b>21</b> displayed very slow fluorophore release under SC-like conditions (98% of the fluorophore released over 15 d). Compound <b>25</b>, a prodrug of the ARV agent raltegravir (RAL), was subsequently prepared and evaluated using the same conditions. This compound showed an excellent in vitro release profile, with a half-life (t<sub>½</sub>) of 19.3 d and 82% of RAL released over 45 d. In mice, <b>25</b> extended the half-life of unmodified RAL by 4.2-fold (t<sub>½</sub> = 3.18 h), providing initial proof of concept of the ability of amino-AOCOM prodrugs to extend drug lifetimes in vivo. Although this effect was not as pronounced as seen in vitro-presumably due to enzymatic degradation and rapid clearance of the prodrug in vivo-the present results nevertheless pave the way for development of more metabolically stable prodrugs, to facilitate long-acting delivery of ARVs. |
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| Item Description: | 10.3390/pharmaceutics15051530 1999-4923 |