Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation
© 2022. The Author(s)..
Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led to an 18-carbon chain modified ester prodrug nanocrystal (coined NM2DTG) with the potential to sustain yearly dosing. Here, we show that the physiochemical and pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injection. Significant plasma drug levels are recorded up to a year following injection. Tissue sites for prodrug hydrolysis are dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affect an extended NM2DTG apparent half-life recorded by PK parameters. The NM2DTG product can impact therapeutic adherence, tolerability, and access of a widely used integrase inhibitor in both resource limited and rich settings to reduce HIV-1 transmission and achieve optimal treatment outcomes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Nature communications - 13(2022), 1 vom: 09. Juni, Seite 3226 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Deodhar, Suyash [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.06.2022 Date Revised 27.07.2023 published: Electronic figshare: 10.6084/m9.figshare.19026452, 10.6084/m9.figshare.19026983, 10.6084/m9.figshare.19027175, 10.6084/m9.figshare.19027229, 10.6084/m9.figshare.19027253, 10.6084/m9.figshare.19362500, 10.6084/m9.figshare.19027397 Citation Status MEDLINE |
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| doi: |
10.1038/s41467-022-30902-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 245 | 1 | 0 | |a Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Revised 27.07.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a figshare: 10.6084/m9.figshare.19026452, 10.6084/m9.figshare.19026983, 10.6084/m9.figshare.19027175, 10.6084/m9.figshare.19027229, 10.6084/m9.figshare.19027253, 10.6084/m9.figshare.19362500, 10.6084/m9.figshare.19027397 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led to an 18-carbon chain modified ester prodrug nanocrystal (coined NM2DTG) with the potential to sustain yearly dosing. Here, we show that the physiochemical and pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injection. Significant plasma drug levels are recorded up to a year following injection. Tissue sites for prodrug hydrolysis are dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affect an extended NM2DTG apparent half-life recorded by PK parameters. The NM2DTG product can impact therapeutic adherence, tolerability, and access of a widely used integrase inhibitor in both resource limited and rich settings to reduce HIV-1 transmission and achieve optimal treatment outcomes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a HIV Integrase Inhibitors |2 NLM | |
| 650 | 7 | |a Heterocyclic Compounds, 3-Ring |2 NLM | |
| 650 | 7 | |a Oxazines |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Prodrugs |2 NLM | |
| 650 | 7 | |a Pyridones |2 NLM | |
| 650 | 7 | |a dolutegravir |2 NLM | |
| 650 | 7 | |a DKO1W9H7M1 |2 NLM | |
| 700 | 1 | |a Sillman, Brady |e verfasserin |4 aut | |
| 700 | 1 | |a Bade, Aditya N |e verfasserin |4 aut | |
| 700 | 1 | |a Avedissian, Sean N |e verfasserin |4 aut | |
| 700 | 1 | |a Podany, Anthony T |e verfasserin |4 aut | |
| 700 | 1 | |a McMillan, JoEllyn M |e verfasserin |4 aut | |
| 700 | 1 | |a Gautam, Nagsen |e verfasserin |4 aut | |
| 700 | 1 | |a Hanson, Brandon |e verfasserin |4 aut | |
| 700 | 1 | |a Dyavar Shetty, Bhagya L |e verfasserin |4 aut | |
| 700 | 1 | |a Szlachetka, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Johnston, Morgan |e verfasserin |4 aut | |
| 700 | 1 | |a Thurman, Michellie |e verfasserin |4 aut | |
| 700 | 1 | |a Munt, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Dash, Alekha K |e verfasserin |4 aut | |
| 700 | 1 | |a Markovic, Milica |e verfasserin |4 aut | |
| 700 | 1 | |a Dahan, Arik |e verfasserin |4 aut | |
| 700 | 1 | |a Alnouti, Yazen |e verfasserin |4 aut | |
| 700 | 1 | |a Yazdi, Alborz |e verfasserin |4 aut | |
| 700 | 1 | |a Kevadiya, Bhavesh D |e verfasserin |4 aut | |
| 700 | 1 | |a Byrareddy, Siddappa N |e verfasserin |4 aut | |
| 700 | 1 | |a Cohen, Samuel M |e verfasserin |4 aut | |
| 700 | 1 | |a Edagwa, Benson |e verfasserin |4 aut | |
| 700 | 1 | |a Gendelman, Howard E |e verfasserin |4 aut | |
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