Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101

• Published in: Journal of pharmaceutical sciences 2020-05, Vol.109 (5), p.1789-1801
• Main Authors: Perazzolo, Simone, Shireman, Laura M., McConnachie, Lisa A., Koehn, Josefin, Kinman, Loren, Lee, Wonsok, Lane, Sarah, Collier, Ann C., Shen, Danny D., Ho, Rodney J.Y.
• Format: Article
• Language: English
• Subjects: AIDS; Animals; Anti-HIV Agents - therapeutic use; Drug Combinations; drug-combination; HIV; HIV Infections - drug therapy; lipid nanoparticle(s) (LNP); long-acting; Lopinavir; Pharmaceutical Preparations; preclinical pharmacokinetics; Ritonavir; targeted drug delivery; targeted therapy
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2020.01.016

TLC-ART101 is a long-acting triple-HIV drug combination of lopinavir-ritonavir-tenofovir in one nanosuspension intended for subcutaneous injection. After a single TLC-ART 101 administration in nonhuman primates, drug concentrations in both plasma and HIV-target lymph node mononuclear cells were sustained for 2 weeks. Nevertheless, the mechanisms leading to the targeted long-acting pharmacokinetics remain elusive. Therefore, an intravenous study of TLC-ART 101 in nonhuman primates was conducted to elucidate the degree of association of drugs in vivo, estimate subcutaneous bioavailability, and refine a mechanism-based pharmacokinetic (MBPK2) model. The MBPK2 model considers TLC-ART 101 systemic drug clearances, nanoparticle-associated/dissociated species, more detailed mechanisms of lymphatic first-pass retention of associated-drugs after subcutaneous administrations, and the prediction of drug concentration time-courses in lymph node mononuclear cells. For all 3 drugs, we found a high association with the nanoparticles in plasma (>87% lopinavir-ritonavir, 97% tenofovir), and an incomplete subcutaneous bioavailability (