期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 107, 期 12, 页码 3153-3162出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2018.07.032
关键词
HIV; AIDS; long-acting; lipid nanoparticle(s) (LNP); drug-combination; preclinical pharmacokinetics; targeted therapy; targeted drug delivery
资金
- Washington National Primate Center Research Support Group
- NIH [UM1 AI120176]
- [P51 OD010425]
- [AI 077390]
Drug-combination nanoparticles (DcNPs) administered subcutaneously represent a potential long-acting lymphatic-targeting treatment for HIV infection. The DcNP containing lopinavir (LPV)-ritonavir (RTV)tenofovir (TFV), Targeted-Long-Acting-Antiretroviral-Therapy product candidate 101 (TLC-ART 101), has shown to provide long-acting lymphocyte-targeting performance in nonhuman primates. To extend the TLC-ART platform, we replaced TLC-ART 101 LPV with second-generation protease inhibitor, atazanavir (ATV). Pharmacokinetics of the ATV-RTV-TFV DcNP was assessed in macaques, in comparison to the equivalent free drug formulation and to the TLC-ART 101. After single subcutaneous administration of the DcNP formulation, ATV, RTV, and TFV concentrations were sustained in plasma for up to 14 days, and in peripheral blood mononuclear cells for 8 to 14 days, compared with 1 to 2 days in those macaques treated with free drug combination. By 1 week, lymph node mononuclear cells showed significant levels for all 3 drugs from DcNPs, whereas the free controls were undetectable. Compared with TLC-ART 101, the ATV-RTV-TFV DcNP exhibited similar lymphocyte-targeted long-acting features for all 3 drugs and similar pharmacokinetics for RTV and TFV, whereas some pharmacokinetic differences were observed for ATV versus LPV. The present study demonstrated the flexibility of the TLC-ART's DcNP platform to include different antiretroviral combinations that produce targeted long-acting effects on both plasma and cells. (c) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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