Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jul;57(7):3110-20.
doi: 10.1128/AAC.00267-13. Epub 2013 Apr 22.

Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy

Nagsen Gautam  1 , Upal Roy, Shantanu Balkundi, Pavan Puligujja, Dongwei Guo, Nathan Smith, Xin-Ming Liu, Benjamin Lamberty, Brenda Morsey, Howard S Fox, Joellyn McMillan, Howard E Gendelman, Yazen Alnouti
Affiliations

Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy

Nagsen Gautam et al. Antimicrob Agents Chemother. 2013 Jul.

Abstract

Long-acting injectable nanoformulated antiretroviral therapy (nanoART) was developed with the explicit goal of improving medicine compliance and for drug targeting of viral tissue reservoirs. Prior nanoART studies completed in humanized virus-infected mice demonstrated sustained antiretroviral responses. However, the pharmacokinetics (PK) and tissue distribution of nanoART were not characterized. To this end, the PK and tissue distribution of nanoformulated atazanavir (ATV) and ritonavir (RTV) injected subcutaneously or intramuscularly in mice and monkeys were evaluated. Fourteen days after injection, ATV and RTV levels were up to 13-, 41-, and 4,500-fold higher than those resulting from native-drug administration in plasma, tissues, and at the site of injection, respectively. At nanoART doses of 10, 50, 100, and 250 mg/kg of body weight, relationships of more- and less-than-proportional increases in plasma and tissue levels with dose increases were demonstrated with ATV and RTV. Multiple-dose regimens showed serum and tissue concentrations up to 270-fold higher than native-drug concentrations throughout 8 weeks of study. Importantly, nanoART was localized in nonlysosomal compartments in tissue macrophages, creating intracellular depot sites. Reflective data were obtained in representative rhesus macaque studies. We conclude that nanoART demonstrates blood and tissue antiretroviral drug levels that are enhanced compared to those of native drugs. The sustained and enhanced PK profile of nanoART is, at least in part, the result of the sustained release of ATV and RTV from tissue macrophases and at the site of injection.

PubMed Disclaimer

Figures

Fig 1
Fig 1
Serum concentration (Conc.) versus time profiles from the acute-dose studies after three ATV doses at days 0, 3, and 7 (A), a single ATV dose at day 0 (B), three RTV doses at days 0, 3, and 7 (C), or a single RTV dose (D). Data show means ± standard errors of the means (SEM) (n = 5); dose = 10 mg/kg.
Fig 2
Fig 2
ATV (A) and RTV (B) serum concentration versus time profiles after 10, 50, 100, and 250 mg/kg nanoART administration on days 0, 3, and 7 in mice (n = 5; data represent means ± SEM).
Fig 3
Fig 3
Serum concentration versus time profiles of ATV (A) and RTV (B) after multiple-dose administration of nanoART and native drugs at 50 mg/kg in mice for 6 weeks. Arrows indicate times of dose administration (n = 6; data represent means ± SEM).
Fig 4
Fig 4
Concentration versus time profiles of ATV in liver (A), kidney (B), spleen (C), lung (D), brain (E), and site of injection (F) after multiple-dose administration of nanoART and native drug for 6 weeks. Doses were administered on days 0, 3, 7, 14, 21, 28, 35, and 42 at 50 mg/kg. Samples were collected right before dose administration on days 7, 14, 21, 28, 35, and 42 in mice (n = 6; data represent means ± SEM).
Fig 5
Fig 5
Concentration versus time profiles of RTV in liver (A), kidney (B), spleen (C), lung (D), brain (E), and site of injection (F) after multiple-dose administration of nanoART and native drug for 6 weeks. Doses were administered on days 0, 3, 7, 14, 21, 28, 35, and 42 at 50 mg/kg. Samples were collected right before dose administration on days 7, 14, 21, 28, 35, and 42 in mice (n = 6; data represent means ± SEM).
Fig 6
Fig 6
ATV (A) and RTV (B) plasma concentration versus time profiles after 50 mg/kg nanoART administration in rhesus macaques (n = 2).
Fig 7
Fig 7
In vivo colocalization of nanoART in CD11b-positive cells of the liver and storage in nonlysosomal compartments. Male BALB/cJ mice were treated SC with 250 mg/kg ATV/RTV (1:1 drug ratio) coated with CF633-modified P188. Liver cells were isolated 24 h later by in situ collagenase digestion. (A) FACS analysis of liver nonparenchymal cells from CF633-P188-ATV/RTV-treated mice incubated with CD11b antibody and collected using MACS cell separation columns. (B) Confocal microscopy of nanoART-loaded nonparenchymal cells following CD11b-positive cell purification showing localization of nanoART (red) in CD11b-positive cells (green) (bar = 20 μm; inset bar = 5 μm). (C) ATV and RTV levels in various liver cell types following cell separation using differential centrifugation and CD11b-positive MACS cell separation (data from a representative experiment are shown). Drug levels were quantitated by LC-MS/MS (bld = below detection limit). (D) Confocal microscopy of nanoART-loaded (red) nonparenchymal cells incubated with Lysotracker Green showing localization of nanoART outside lysosomal (green) compartments (bar = 10 μm).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ellis R, Langford D, Masliah E. 2007. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat. Rev. Neurosci. 8:33–44 - PubMed
    1. Work Group for HIV and Aging Consensus Project 2012. Summary report from the Human Immunodeficiency Virus and Aging Consensus Project: treatment strategies for clinicians managing older individuals with the human immunodeficiency virus. J. Am. Geriatr. Soc. 60:974–979 - PubMed
    1. Pasternak AO, de Bruin M, Jurriaans S, Bakker M, Berkhout B, Prins JM, Lukashov VV. 2012. Modest nonadherence to antiretroviral therapy promotes residual HIV-1 replication in the absence of virological rebound in plasma. J. Infect. Dis. 206:1443–1452 - PubMed
    1. Coiras M, Lopez-Huertas MR, Alcami J. 2010. HIV-1 latency and eradication of long-term viral reservoirs. Discov. Med. 9:185–191 - PubMed
    1. Rao KS, Ghorpade A, Labhasetwar V. 2009. Targeting anti-HIV drugs to the CNS. Expert Opin. Drug Deliv. 6:771–784 - PMC - PubMed

Publication types

MeSH terms