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.
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 (<29% lopinavir-ritonavir, 85% tenofovir). As hypothesized by the MBPK2 model, the incomplete SC bioavailability observed is due to sequestration into a lymphatic node depot after subcutaneous absorption (unlike most intramuscular nanodrug products having near-to-injection depots), which contributes to long-acting profiles detected in plasma and target cells. This combined experimental and modeling approach may be applicable for the clinical development of other long-acting drug-combination injectables.
['Perazzolo|Simone|S|', 'Shireman|Laura M|LM|', 'McConnachie|Lisa A|LA|', 'Koehn|Josefin|J|', 'Kinman|Loren|L|', 'Lee|Wonsok|W|', 'Lane|Sarah|S|', 'Collier|Ann C|AC|', 'Shen|Danny D|DD|', 'Ho|Rodney J Y|RJY|']
D000818:Animals D019380:Anti-HIV Agents D004338:Drug Combinations D015658:HIV Infections D061466:Lopinavir D004364:Pharmaceutical Preparations D019438:Ritonavir
long-acting drug-combination 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) (PubChem CID: 94190) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt) (DSPE-mPEG(2000)) (PubChem CID: 406952) AIDS HIV Lopinavir (PubChem CID: 92727) lipid nanoparticle(s) (LNP) preclinical pharmacokinetics ritonavir (PubChem CID: 392622) targeted drug delivery targeted therapy tenofovir (PubChem CID: 464205)