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

    Department of Bioengineering, University of Washington, Seattle, Washington, 98195
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Published:October 18, 2021DOI:


      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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        • Hayward P.
        Highlights of virtual CROI 2021.
        The Lancet HIV. 2021; 8: e184
        • Kazi F
        • Mushtaq A.
        CROI 2021.
        The Lancet Infectious Diseases. 2021; 21: 606
        • Akinwunmi B
        • Buchenberger D
        • Scherzer J
        • et al.
        Factors associated with interest in a long-acting HIV regimen: perspectives of people living with HIV and healthcare providers in four European countries.
        Sex Transm Infect. 2021; 25 (Published online February)
        • Philbin MM
        • Parish C
        • Bergen S
        • et al.
        A Qualitative Exploration of Women's Interest in Long-Acting Injectable Antiretroviral Therapy Across Six Cities in the Women's Interagency HIV Study: Intersections with Current and Past Injectable Medication and Substance Use.
        AIDS Patient Care and STDs. 2021; 35: 23-30
        • Weld ED
        • Flexner C.
        Long-acting implants to treat and prevent HIV infection.
        Curr Opin HIV AIDS. 2020; 15: 33-41
        • Flexner C
        • Owen A
        • Siccardi M
        • Swindells S.
        Long-acting drugs and formulations for the treatment and prevention of HIV infection.
        International Journal of Antimicrobial Agents. 2021; 57106220
        • Perazzolo S
        • Shireman LM
        • Koehn J
        • et al.
        Three HIV Drugs, Atazanavir, Ritonavir, and Tenofovir, Coformulated in Drug-Combination Nanoparticles Exhibit Long-Acting and Lymphocyte-Targeting Properties in Nonhuman Primates.
        JPharmSci. 2018; 107: 3153-3162
        • KOEHN J
        • IWAMOTO JF
        • KRAFT JC
        • McCONNACHIE LA
        • COLLIER AC
        • HO RJY
        Extended cell and plasma drug levels after one dose of a 3-in-1 nanosuspension containing lopinavir, efavirenz, and tenofovir in non-human primates.
        AIDS. 2018; 32: 2463-2467
        • McConnachie LA
        • Kinman LM
        • Koehn J
        • et al.
        Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection.
        JPharmSci. 2018; 107: 1787-1790
        • Perazzolo S
        • Shireman LM
        • McConnachie LA
        • et al.
        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.
        JPharmSci. 2020; 109: 1789-1801
        • Freeling JP
        • Koehn J
        • Shu C
        • Sun J
        • Ho RJY.
        Anti-HIV Drug-Combination Nanoparticles Enhance Plasma Drug Exposure Duration as Well as Triple-Drug Combination Levels in Cells Within Lymph Nodes and Blood in Primates.
        AIDS Res Hum Retroviruses. 2015; 31: 107-114
        • Yu J
        • Mu Q
        • Perazzolo S
        • et al.
        Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules.
        Pharmaceutical Research. 2020; 37: 197
        • Yu J
        • Yu D
        • Lane S
        • McConnachie L
        • Ho RJY.
        Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir.
        Journal of Pharmaceutical Sciences. 2020; (Published online August 10)
        • Kraft JC
        • McConnachie LA
        • Koehn J
        • et al.
        Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation.
        Journal of Controlled Release. 2018; 275: 229-241
        • Kraft JC
        • McConnachie LA
        • Koehn J
        • et al.
        Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma.
        AIDS. 2017; 31: 765-770
        • Koehn J
        • Ho RJY.
        Novel liquid chromatography-tandem mass spectrometry method for simultaneous detection of anti-HIV drugs Lopinavir, Ritonavir, and Tenofovir in plasma.
        Antimicrob Agents Chemother. 2014; 58: 2675-2680
        • Sarin H.
        Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability.
        J Angiogenes Res. 2010; 2: 14
        • Rippe B
        • Haraldsson B.
        Fluid and protein fluxes across small and large pores in the microvasculature. Application of two-pore equations.
        Acta Physiologica Scandinavica. 1987; 131: 411-428
        • Gill KL
        • Gardner I
        • Li L
        • Jamei M.
        A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins.
        AAPS J. 2016; 18: 156-170
        • Bui T
        • Stevenson J
        • Hoekman J
        • Zhang S
        • Maravilla K
        • Ho RJY.
        Novel Gd Nanoparticles Enhance Vascular Contrast for High-Resolution Magnetic Resonance Imaging.
        PLoS One. 2010; 5
        • Reddy ST
        • Berk DA
        • Jain RK
        • Swartz MA.
        A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles.
        J Appl Physiol (1985). 2006; 101: 1162-1169
        • Ager A.
        High Endothelial Venules.
        in: Delves PJ Encyclopedia of Immunology (Second Edition). Elsevier, 1998: 1093-1101
        • Young AJ.
        The physiology of lymphocyte migration through the single lymph node in vivo.
        Seminars in Immunology. 1999; 11: 73-83
        • Hunter MC
        • Teijeira A
        • Halin C.
        T Cell Trafficking through Lymphatic Vessels.
        Front Immunol. 2016; 7
        • Ganusov VV
        • Auerbach J.
        Mathematical modeling reveals kinetics of lymphocyte recirculation in the whole organism.
        PLoS Comput Biol. 2014; 10e1003586
        • Ibrahim R
        • Nitsche JM
        • Kasting GB.
        Dermal clearance model for epidermal bioavailability calculations.
        J Pharm Sci. 2012; 101: 2094-2108
        • Hollander W
        • Reilly P
        • Burrows BA.
        J Clin Invest. 1961; 40: 222-233
        • Ellis JP
        • Marks R
        • Perry BJ.
        Lymphatic Function: The Disappearance Rate of 131i Albumin from the Dermis.
        British Journal of Dermatology. 1970; 82: 593-599
        • Fernandez MJ
        • Davies WT
        • Owen GM
        • Tyler A.
        Lymphatic flow in humans as indicated by the clearance of 125I-labeled albumin from the subcutaneous tissue of the leg.
        Journal of Surgical Research. 1983; 35: 101-104
        • Staberg B
        • Klemp P
        • Aasted M
        • Worm A-M
        • Lund P.
        Lymphatic albumin clearance from psoriatic skin.
        Journal of the American Academy of Dermatology. 1983; 9: 857-861
        • Kelch ID
        • Bogle G
        • Sands GB
        • Phillips ARJ
        • LeGrice IJ
        • Dunbar PR.
        High-resolution 3D imaging and topological mapping of the lymph node conduit system.
        PLOS Biology. 2019; 17e3000486
        • Baas J
        • Senninger N
        • Elser H.
        [The reticuloendothelial system. An overview of function, pathology and recent methods of measurement].
        Z Gastroenterol. 1994; 32: 117-123
        • Perazzolo S
        • Zhu L
        • Lin W
        • Nguyen A
        • Ho RJY.
        Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective.
        Journal of Pharmaceutical Sciences. 2021; 110: 1002-1017
        • Perazzolo S
        • Mandal S
        • Prathipati PK
        • Destache CJ.
        Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments.
        Frontiers in Pharmacology. 2020; : 11
        • Kraft JC
        • Treuting PM
        • Ho RJY.
        Indocyanine green nanoparticles undergo selective lymphatic uptake, distribution and retention and enable detailed mapping of lymph vessels, nodes and abnormalities.
        Journal of Drug Targeting. 2018; 26: 494-504
        • Förster R
        • Braun A
        • Worbs T.
        Lymph node homing of T cells and dendritic cells via afferent lymphatics.
        Trends in Immunology. 2012; 33: 271-280
        • Frost H
        • Cahill RNP
        • Trnka Z.
        The migration of recirculating autologous and allogeneic lymphocytes through single lymph nodes.
        European Journal of Immunology. 1975; 5: 839-843
        • Reynolds J
        • Heron I
        • Dudler L
        • Trnka Z.
        T-cell recirculation in the sheep: migratory properties of cells from lymph nodes.
        Immunology. 1982; 47: 415-421
        • Smith ME
        • Ford WL.
        The recirculating lymphocyte pool of the rat: a systematic description of the migratory behaviour of recirculating lymphocytes.
        Immunology. 1983; 49: 83-94
        • Westermann J
        • Söllner S
        • Ehlers E-M
        • Nohroudi K
        • Blessenohl M
        • Kalies K.
        Analyzing the Migration of Labeled T Cells In Vivo : An Essential Approach with Challenging Features.
        Laboratory Investigation. 2003; 83: 459-469
        • Di Mascio M
        • Paik CH
        • Carrasquillo JA
        • et al.
        Noninvasive in vivo imaging of CD4 cells in simian-human immunodeficiency virus (SHIV)-infected nonhuman primates.
        Blood. 2009; 114: 328-337
        • Butcher EC.
        • et al.
        The Regulation of Lymphocyte Traffic.
        in: Clarke A Compans RW Cooper M Current Topics in Microbiology and Immunology. Current Topics in Microbiology and Immunology. Springer, 1986: 85-122
      1. Gilead Sciences. Drug Approval Package: VIREAD (Tenofovir Disoproxil Fumarate) Tablets. Published 2001. Accessed October 30, 2020.

        • Zhu Y
        • Curtis M
        • Qi X
        • Miller MD
        • Borroto-Esoda K.
        Anti-hepatitis B virus activity in vitro of combinations of tenofovir with nucleoside/nucleotide analogues.
        Antivir Chem Chemother. 2009; 19: 165-176
        • Bollinger RC
        • Thio CL
        • Sulkowski MS
        • McKenzie-White J
        • Thomas DL
        • Flexner C.
        Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV.
        Lancet HIV. 2020; 7: e443-e448
        • Perelson AS
        • Wiegel FW.
        Scaling aspects of lymphocyte trafficking.
        Journal of Theoretical Biology. 2009; 257: 9-16