Lipid-drug association enhanced HIV-1 protease inhibitor indinavir localization in lymphoid tissues and viral load reduction: a proof of concept study in HIV-2287-infected macaques.
Analysis of indinavir levels in HIV-positive patients indicated that drug concentrations in lymph node mononuclear cells (LNMCs) were about 25-35% of mononuclear cells in blood. To enhance lymphatic delivery of anti-HIV drugs, a novel drug delivery strategy was designed consisting of lipid-associated indinavir (50-80 nm in diameter) complexes in suspension for subcutaneous (SC) injection. Due to the pH-dependent lipophilicity of indinavir, practically all the drug molecules are incorporated into lipid phase when formulated at pH 7.4 and 5:1 lipid-to-drug (m/m) ratio. At pH 5.5, about 20% of drugs were found in lipid-drug complexes. Effects of lipid association on the time course of plasma indinavir concentrations were determined in macaques (Macaca nemestrina) administered with either soluble or lipid-associated formulation of indinavir (10 mg/kg, SC). Results yielded about a 10-fold reduction in peak plasma concentration and a 6-fold enhancement in terminal half-life (t1/2beta = 12 vs. 2 hours). In addition, indinavir concentrations in both peripheral and visceral lymph nodes were 250-2270% higher than plasma (compared with <35% with soluble lipid-free drug administration in humans). Administration of lipid-associated indinavir (20 mg/kg daily) to HIV-2287-infected macaques (at 30-33 weeks after infection) resulted in significantly reduced viral RNA load and increased CD4 T cell number concentrations. Collectively, these data indicate that lipid association greatly enhances delivery of the anti-HIV drug indinavir to lymph nodes at levels that cannot be achieved with soluble drug, provides significant virus load reduction, and could potentially reverse CD4 T cell depletion due to HIV infection.
Kinman
Loren
L
Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
Brodie
Scott J
SJ
Tsai
Che Chung
CC
Bui
Tot
T
Larsen
Kay
K
Schmidt
Ann
A
Anderson
David
D
Morton
William R
WR
Hu
Shiu-Lok
SL
Ho
Rodney J Y
RJ
D000818:Animals; D018791:CD4 Lymphocyte Count; D002784:Cholesterol / Q000097:blood; D018450:Disease Progression; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015498:HIV-2 / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D019469:Indinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008081:Liposomes; D008221:Lymphoid Tissue / Q000378:metabolism* / Q000821:virology; D008251:Macaca; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D017320:HIV Protease Inhibitors; D008081:Liposomes; D012367:RNA, Viral; D019469:Indinavir; D002784:Cholesterol