@article{8b2095aa9b784687a56c91570cd42347,
title = "Lipophilic nanocrystal prodrug-release defines the extended pharmacokinetic profiles of a year-long cabotegravir",
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.",
author = "Nagsen Gautam and McMillan, {Jo Ellyn M.} and Devendra Kumar and Bade, {Aditya N.} and Qiaoyu Pan and Kulkarni, {Tanmay A.} and Wenkuan Li and Brady Sillman and Smith, {Nathan A.} and Shetty, {Bhagya L.Dyavar} and Adam Szlachetka and Edagwa, {Benson J.} and Gendelman, {Howard E.} and Yazen Alnouti",
note = "Funding Information: We thank the University of Nebraska Medical Center (UNMC) Elutriation and Cell Separation Core (Myhanh Che and Na Ly) for providing human monocytes. We are thankful to Benjamin G. Lamberty, Brenda M. Morsey, and Dr. Howard Fox for the extension of previously published data sets performed with NM2CAB in rhesus macaques (in Nat Mater. 2020 Aug;19(8):910-920). The work was supported, in part, by the University of Nebraska Foundation, which includes donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, the Frances and Louie Blumkin, and the Harriet Singer Research Donations. We thank Dr. Bradley Britigan, Dean of the College of Medicine at UNMC, for providing funds to support the Covance studies. The authors thank Sarah Favara, Emily Archer and the Covance Laboratory staff that assisted in conducting and analyzing the data sets for rigor and reproducibility. We thank Dr. Jennifer Larsen, the Vice Chancellor for Research for UNMC for Core research support enabling continuance of this work. The research also received support from National Institutes of Health grants PO1 DA028555, R01 NS36126, PO1 MH64570, P30 MH062261, R01 AG043540, and 2R01 NS034239. We also thank the INBRE grant support from 2P20GM103427 for infrastructure research support. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-23668-x",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}