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Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 2: Model for the Drug-combination Nanoparticles

  • Simone Perazzolo
    Correspondence
    Corresponding Authors: Prof. Rodney J.Y. Ho, University of Washington, Seattle, WA 98195-7610, USA, Phone: 206-543-9434
    Affiliations
    Department of Pharmaceutics, University of Washington, Seattle, Washington, 98195
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  • Danny D. Shen
    Affiliations
    Department of Pharmaceutics, University of Washington, Seattle, Washington, 98195
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  • Rodney J.Y. Ho
    Correspondence
    Corresponding Authors: Prof. Rodney J.Y. Ho, University of Washington, Seattle, WA 98195-7610, USA, Phone: 206-543-9434
    Affiliations
    Department of Pharmaceutics, University of Washington, Seattle, Washington, 98195

    Department of Bioengineering, University of Washington, Seattle, Washington, 98195
    Search for articles by this author
Published:October 18, 2021DOI:https://doi.org/10.1016/j.xphs.2021.10.009

      Abstract

      We previously developed a mechanism-based pharmacokinetic (MBPK) model to characterize the PK of a lymphocyte-targeted, long-acting 3 HIV drug-combination nanoparticle (DcNP) formulation of lopinavir, ritonavir, and tenofovir. MBPK describes time-courses of plasma drug concentration and has provided an initial hypothesis for the lymphatic PK of DcNP. Because anatomical and physiological interpretation of MBPK is limited, in this Part 2, we report the development of a Physiologically Based Pharmacokinetic (PBPK) model for a detailed evaluation of the lymphatic and tissue PK of drugs associated with DcNP. The DcNP model is linked to the PBPK model presented earlier in Part 1 to account for the disposition of released free drugs. A key feature of the DcNP model is the uptake of the injected dose from the subcutaneous site to the adjacent lymphoid depot, routing through the nodes within and throughout the lymphatic network, and its subsequent passage into the blood circulation. Furthermore, the model accounts for DcNP transport to the lymph by lymphatic recirculation and mononuclear cell migration. The present PBPK model can be extended to other nano-drug combinations that target or transit through the lymphatic system. The PBPK model may allow scaling and prediction of DcNP PK in humans.

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