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, Brady Sillman, Nathan A. Smith, Bhagya L. Dyavar Shetty, Adam Szlachetka, Benson J. Edagwa, Howard E. Gendelman () and Yazen Alnouti ()
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Nagsen Gautam: University of Nebraska Medical Center
JoEllyn M. McMillan: University of Nebraska Medical Center
Devendra Kumar: University of Nebraska Medical Center
Aditya N. Bade: University of Nebraska Medical Center
Qiaoyu Pan: University of Nebraska Medical Center
Tanmay A. Kulkarni: University of Nebraska Medical Center
Wenkuan Li: University of Nebraska Medical Center
Brady Sillman: University of Nebraska Medical Center
Nathan A. Smith: University of Nebraska Medical Center
Bhagya L. Dyavar Shetty: University of Nebraska Medical Center
Adam Szlachetka: University of Nebraska Medical Center
Benson J. Edagwa: University of Nebraska Medical Center
Howard E. Gendelman: University of Nebraska Medical Center
Yazen Alnouti: University of Nebraska Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract A 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 advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility.

Date: 2021
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DOI: 10.1038/s41467-021-23668-x

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