title: Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma.
abstract: The aim of the present study was to determine whether a combination of anti-HIV drugs - tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) - in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma.
  
  
  
  Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC-MS/MS assay.
  
  
  
  For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF).
  
  
  
  A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes.
authors.affiliation: aDepartment of Pharmaceutics bDepartment of Medicine cCenter for AIDS Research dDepartment of Bioengineering, University of Washington, Seattle, Washington, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Kraft
authors.forename: Lisa A
authors.initials: LA
authors.lastname: McConnachie
authors.forename: Josefin
authors.initials: J
authors.lastname: Koehn
authors.forename: Loren
authors.initials: L
authors.lastname: Kinman
authors.forename: Carol
authors.initials: C
authors.lastname: Collins
authors.forename: Danny D
authors.initials: DD
authors.lastname: Shen
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Rodney J Y
authors.initials: RJ
authors.lastname: Ho
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D001773:Blood Cells / Q000737:chemistry*; D002853:Chromatography, Liquid; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008198:Lymph Nodes / Q000737:chemistry*; D008251:Macaca; D010949:Plasma / Q000737:chemistry*; D013535:Suspensions / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D013535:Suspensions