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Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir

Nagsen Gautam, JoEllyn M. McMillan, Devendra Kumar, Aditya N. Bade, Qiaoyu Pan, Tanmay A. Kulkarni, Wenkuan Li, Nathan A Smith, Bhagya L. Dyavar Shetty, Brady Sillman, Adam Szlachetka, Benson J. Edagwa, Howard E. Gendelman, Yazen Alnouti
doi: https://doi.org/10.1101/2021.01.18.427147
Nagsen Gautam
aDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA
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JoEllyn M. McMillan
bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Devendra Kumar
aDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Aditya N. Bade
bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Qiaoyu Pan
aDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Tanmay A. Kulkarni
aDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Wenkuan Li
aDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Nathan A Smith
bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Bhagya L. Dyavar Shetty
bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Brady Sillman
bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Adam Szlachetka
cNebraska Nanomedicine Production Plant, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Benson J. Edagwa
bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA
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Howard E. Gendelman
aDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA
bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA
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  • For correspondence: yalnouti@unmc.edu hegendel@unmc.edu
Yazen Alnouti
aDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA
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  • For correspondence: yalnouti@unmc.edu hegendel@unmc.edu
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Abstract

A single, once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable can advance efforts leading to the elimination of viral transmission. The current submission adds rigor, reproducibility and mechanistic insights for the extended apparent half-life of a yearlong antiretroviral injectable. Pharmacokinetic (PK) profiles of a nanoformulated fatty acid ester CAB prodrug (named NM2CAB) were affirmed at two academic and one contract research laboratory. PK profiles showed plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for up to one year after a single dose. Measures of drug biodistribution demonstrated sustained native drug at the muscle injection site and in lymphoid tissues (spleen and lymph nodes). The results paralleled NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals were stable in blood, tissue and liver homogenates. The long apparent drug half-life followed pH-dependent slow prodrug release in weeks from the nanocrystal. In contrast, solubilized prodrug was hydrolyzed in hours in plasma and tissues recorded from multiple mammalian species at basic pH. No measurable toxicities were recorded. These results, taken together, affirm the pharmacological mechanistic properties of a year-long nanoformulated CAB prodrug supporting the established protocol design for formulation safety, rigor and reproducibility.

Competing Interest Statement

Benson Edagwa and Howard E. Gendelman are cofounders of Exavir Therapeutics, Inc. and are inventors on a patent that cover yearlong integrase inhibitor prodrug formulations (PCT/US2019/057406, WO2020-086555).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 19, 2021.
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Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir
Nagsen Gautam, JoEllyn M. McMillan, Devendra Kumar, Aditya N. Bade, Qiaoyu Pan, Tanmay A. Kulkarni, Wenkuan Li, Nathan A Smith, Bhagya L. Dyavar Shetty, Brady Sillman, Adam Szlachetka, Benson J. Edagwa, Howard E. Gendelman, Yazen Alnouti
bioRxiv 2021.01.18.427147; doi: https://doi.org/10.1101/2021.01.18.427147
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Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir
Nagsen Gautam, JoEllyn M. McMillan, Devendra Kumar, Aditya N. Bade, Qiaoyu Pan, Tanmay A. Kulkarni, Wenkuan Li, Nathan A Smith, Bhagya L. Dyavar Shetty, Brady Sillman, Adam Szlachetka, Benson J. Edagwa, Howard E. Gendelman, Yazen Alnouti
bioRxiv 2021.01.18.427147; doi: https://doi.org/10.1101/2021.01.18.427147

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