Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation

Suyash Deodhar; Brady Sillman; Aditya N. Bade; Sean N. Avedissian; Anthony T. Podany; Jo Ellyn M. McMillan; Nagsen Gautam; Brandon Hanson; Bhagya L. Dyavar Shetty; Adam Szlachetka; Morgan Johnston; Michellie Thurman; Daniel J. Munt; Alekha K. Dash; Milica Markovic; Arik Dahan; Yazen Alnouti; Alborz Yazdi; Bhavesh D. Kevadiya; Siddappa N. Byrareddy; Samuel M. Cohen; Benson Edagwa; Howard E. Gendelman

doi:10.1038/s41467-022-30902-7

Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation

Suyash Deodhar, Brady Sillman, Aditya N. Bade, Sean N. Avedissian, Anthony T. Podany, Jo Ellyn M. McMillan, Nagsen Gautam, Brandon Hanson, Bhagya L. Dyavar Shetty, Adam Szlachetka, Morgan Johnston, Michellie Thurman, Daniel J. Munt, Alekha K. Dash, Milica Markovic, Arik Dahan, Yazen Alnouti, Alborz Yazdi, Bhavesh D. Kevadiya, Siddappa N. ByrareddySamuel M. Cohen, Benson Edagwa, Howard E. Gendelman

Department of Clinical Biochemistry and Pharmacology

Ben-Gurion University of the Negev

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	American English
Article number	3226
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30902-7
State	Published - 1 Dec 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 5 Gender Equality

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-022-30902-7

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Deodhar, S., Sillman, B., Bade, A. N., Avedissian, S. N., Podany, A. T., McMillan, J. E. M., Gautam, N., Hanson, B., Dyavar Shetty, B. L., Szlachetka, A., Johnston, M., Thurman, M., Munt, D. J., Dash, A. K., Markovic, M., Dahan, A., Alnouti, Y., Yazdi, A., Kevadiya, B. D., ... Gendelman, H. E. (2022). Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation. Nature Communications, 13(1), Article 3226. https://doi.org/10.1038/s41467-022-30902-7

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title = "Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation",

abstract = "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.",

author = "Suyash Deodhar and Brady Sillman and Bade, {Aditya N.} and Avedissian, {Sean N.} and Podany, {Anthony T.} and McMillan, {Jo Ellyn M.} and Nagsen Gautam and Brandon Hanson and {Dyavar Shetty}, {Bhagya L.} and Adam Szlachetka and Morgan Johnston and Michellie Thurman and Munt, {Daniel J.} and Dash, {Alekha K.} and Milica Markovic and Arik Dahan and Yazen Alnouti and Alborz Yazdi and Kevadiya, {Bhavesh D.} and Byrareddy, {Siddappa N.} and Cohen, {Samuel M.} and Benson Edagwa and Gendelman, {Howard E.}",

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Deodhar, S, Sillman, B, Bade, AN, Avedissian, SN, Podany, AT, McMillan, JEM, Gautam, N, Hanson, B, Dyavar Shetty, BL, Szlachetka, A, Johnston, M, Thurman, M, Munt, DJ, Dash, AK, Markovic, M, Dahan, A, Alnouti, Y, Yazdi, A, Kevadiya, BD, Byrareddy, SN, Cohen, SM, Edagwa, B & Gendelman, HE 2022, 'Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation', Nature Communications, vol. 13, no. 1, 3226. https://doi.org/10.1038/s41467-022-30902-7

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T1 - Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation

AU - Deodhar, Suyash

AU - Sillman, Brady

AU - Bade, Aditya N.

AU - Avedissian, Sean N.

AU - Podany, Anthony T.

AU - McMillan, Jo Ellyn M.

AU - Gautam, Nagsen

AU - Hanson, Brandon

AU - Dyavar Shetty, Bhagya L.

AU - Szlachetka, Adam

AU - Johnston, Morgan

AU - Thurman, Michellie

AU - Munt, Daniel J.

AU - Dash, Alekha K.

AU - Markovic, Milica

AU - Dahan, Arik

AU - Alnouti, Yazen

AU - Yazdi, Alborz

AU - Kevadiya, Bhavesh D.

AU - Byrareddy, Siddappa N.

AU - Cohen, Samuel M.

AU - Edagwa, Benson

AU - Gendelman, Howard E.

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-022-30902-7

M3 - Article

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SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3226

ER -

Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation

Abstract

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