title: Evaluation of atazanavir and darunavir interactions with lipids for developing pH-responsive anti-HIV drug combination nanoparticles.
abstract: We evaluated two human immunodeficiency virus (HIV) protease inhibitors, atazanavir (ATV) and darunavir (DRV), for pH-dependent solubility, lipid binding, and drug release from lipid nanoparticles (LNPs). Both ATV and DRV incorporated into LNPs composed of pegylated and non-pegylated phospholipids with nearly 100% efficiency, but only ATV-LNPs formed stable lipid-drug particles and exhibited pH-dependent drug release. DRV-LNPs were unstable and formed mixed micelles at low drug-lipid concentrations, and thus are not suitable for lipid-drug particle development. When ATV-LNPs were prepared with ritonavir (RTV), a metabolic and cellular membrane exporter inhibitor, and tenofovir (TFV), an HIV reverse-transcriptase inhibitor, stable, scalable, and reproducible anti-HIV drug combination LNPs were produced. Drug incorporation efficiencies of 85.5 ± 8.2, 85.1 ± 7.1, and 6.1 ± 0.8% for ATV, RTV, and TFV, respectively, were achieved. Preliminary primate pharmacokinetic studies with these pH-responsive anti-HIV drug combination LNPs administered subcutaneously produced detectable plasma concentrations that lasted for 7 days for all three drugs. These anti-HIV LNPs could be developed as a long-acting targeted antiretroviral therapy.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, 98195-7610.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Duan
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Freeling
authors.forename: Josefin
authors.initials: J
authors.lastname: Koehn
authors.forename: Cuiling
authors.initials: C
authors.lastname: Shu
authors.forename: Rodney J Y
authors.initials: RJ
authors.lastname: Ho
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D000069446:Atazanavir Sulfate; D000069454:Darunavir; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004338:Drug Combinations; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry*; D008254:Macaca nemestrina; D009842:Oligopeptides / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D063065:Organophosphonates / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D008055:Lipids; D009842:Oligopeptides; D063065:Organophosphonates; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; D000225:Adenine; D000069454:Darunavir
keywords: HIV; lipid-drug interactions; long acting; nanotechnology; pharmacokinetics; physical characterization; primate; stabilization; targeted drug delivery