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Research Article Pharmacokinetics, Pharmacodynamics and Drug Transport and Metabolism| Volume 109, ISSUE 5, P1789-1801, May 01, 2020

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

  • Simone Perazzolo
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Laura M. Shireman
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Lisa A. McConnachie
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Josefin Koehn
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Loren Kinman
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Wonsok Lee
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Sarah Lane
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Ann C. Collier
    Affiliations
    Department of Medicine, University of Washington, Seattle, Washington 98195

    Center for AIDS Research, University of Washington, Seattle, Washington 98195
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  • Danny D. Shen
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195
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  • Rodney J.Y. Ho
    Correspondence
    Correspondence to: Rodney J.Y. Ho (Telephone: +1-206-543-3796).
    Affiliations
    Department of Pharmaceutics and Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, Washington 98195

    Department of Bioengineering, University of Washington, Seattle, Washington 98195
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Published:January 29, 2020DOI:https://doi.org/10.1016/j.xphs.2020.01.016

      Abstract

      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.

      Keywords

      Chemical compounds studied in this article

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