title: Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.forename: Upal
authors.initials: U
authors.lastname: Roy
authors.forename: Shantanu
authors.initials: S
authors.lastname: Balkundi
authors.forename: Pavan
authors.initials: P
authors.lastname: Puligujja
authors.forename: Dongwei
authors.initials: D
authors.lastname: Guo
authors.forename: Nathan
authors.initials: N
authors.lastname: Smith
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Liu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lamberty
authors.forename: Brenda
authors.initials: B
authors.lastname: Morsey
authors.forename: Howard S
authors.initials: HS
authors.lastname: Fox
authors.forename: Joellyn
authors.initials: J
authors.lastname: McMillan
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir