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Physiologically Based Pharmacokinetic (PBPK) Modeling of Pharmaceutical Nanoparticles

  • Review Article
  • Theme: Nanotechnology in Complex Drug Products: Learning from the Past, Preparing for the Future
  • Published:
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Abstract

With the great interests in the discovery and development of drug products containing nanoparticles, there is a great demand of quantitative tools for assessing quality, safety, and efficacy of these products. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches provide excellent tools for describing and predicting in vivo absorption, distribution, metabolism, and excretion (ADME) of nanoparticles administered through various routes. PBPK modeling of nanoparticles is an emerging field, and more than 20 PBPK models of nanoparticles used in pharmaceutical products have been published in the past decade. This review provides an overview of the ADME characteristics of nanoparticles and how these ADME processes are described in PBPK models. Recent advances in PBPK modeling of pharmaceutical nanoparticles are summarized. The major challenges in model development and validation and possible solutions are also discussed.

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References

  1. Zhao P, Rowland M, Huang SM. Best practice in the use of physiologically based pharmacokinetic modeling and simulation to address clinical pharmacology regulatory questions. Clin Pharmacol Ther. 2012;92(1):17–20.

    Article  CAS  PubMed  Google Scholar 

  2. Zhao P et al. Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review. Clin Pharmacol Ther. 2011;89(2):259–67.

    Article  CAS  PubMed  Google Scholar 

  3. Li M et al. Physiologically based pharmacokinetic modeling of nanoparticles. ACS Nano. 2010;4(11):6303–17.

    Article  CAS  PubMed  Google Scholar 

  4. Harashima H et al. Optimization of antitumor effect of liposomally encapsulated doxorubicin based on simulations by pharmacokinetic/pharmacodynamic modeling. J Control Release. 1999;61(1–2):93–106.

    Article  CAS  PubMed  Google Scholar 

  5. Pery AR et al. Development of a physiologically based kinetic model for 99m-technetium-labelled carbon nanoparticles inhaled by humans. Inhal Toxicol. 2009;21(13):1099–107.

    Article  PubMed  Google Scholar 

  6. Li M et al. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content. Int J Nanomed. 2012;7:1345–56.

    CAS  Google Scholar 

  7. Bachler G, von Goetz N, Hungerbuhler K. A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles. Int J Nanomed. 2013;8:3365–82.

    Google Scholar 

  8. Lee HA et al. Comparison of quantum dot biodistribution with a blood-flow-limited physiologically based pharmacokinetic model. Nano Lett. 2009;9(2):794–9.

    Article  CAS  PubMed  Google Scholar 

  9. Lin P et al. Computational and ultrastructural toxicology of a nanoparticle, quantum dot 705, in mice. Environ Sci Technol. 2008;42(16):6264–70.

    Article  CAS  PubMed  Google Scholar 

  10. Opitz AW et al. Physiologically based pharmacokinetics of molecular imaging nanoparticles for mRNA detection determined in tumor-bearing mice. Oligonucleotides. 2010;20(3):117–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mager DE et al. Physiologically based pharmacokinetic model for composite nanodevices: effect of charge and size on in vivo disposition. Pharm Res. 2012;29(9):2534–42.

    Article  CAS  PubMed  Google Scholar 

  12. Kagan L et al. Dual physiologically based pharmacokinetic model of liposomal and nonliposomal amphotericin B disposition. Pharm Res. 2014;31(1):35–45.

    Article  CAS  PubMed  Google Scholar 

  13. des Rieux A et al. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release. 2006;116(1):1–27.

    Article  PubMed  Google Scholar 

  14. Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 2005;113(7):823–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. MacCalman LT, Tran CL, Kuempel E. Development of a bio-mathematical model in rats to describe clearance, retention and translocation of inhaled nano particles throughout the body. J Phys Conf Ser. 2009;151:1–10.

    Article  Google Scholar 

  16. Bachler G, von Goetz N, Hungerbuhler K. Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO2) nanoparticles. Nanotoxicology. 2015;9(3):373–80.

    Article  CAS  PubMed  Google Scholar 

  17. Bachler G et al. Translocation of gold nanoparticles across the lung epithelial tissue barrier: combining in vitro and in silico methods to substitute in vivo experiments. Part Fibre Toxicol. 2015;12:18.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sweeney LM et al. Bayesian evaluation of a physiologically-based pharmacokinetic (PBPK) model of long-term kinetics of metal nanoparticles in rats. Regul Toxicol Pharmacol. 2015;73(1):151–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rajoli RK et al. Physiologically based pharmacokinetic modelling to inform development of intramuscular long-acting nanoformulations for HIV. Clin Pharmacokinet. 2015;54(6):639–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.

    Article  CAS  PubMed  Google Scholar 

  21. Salvati A et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol. 2013;8(2):137–43.

    Article  CAS  PubMed  Google Scholar 

  22. Gao H, He Q. The interaction of nanoparticles with plasma proteins and the consequent influence on nanoparticles behavior. Exp Opin Drug Deliv. 2014;11(3):409–20.

    Article  CAS  Google Scholar 

  23. Aggarwal P et al. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliv Rev. 2009;61(6):428–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33(9):941–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mahmoudi M et al. Protein-nanoparticle interactions: opportunities and challenges. Chem Rev. 2011;111(9):5610–37.

    Article  CAS  PubMed  Google Scholar 

  26. Kobayashi H, Watanabe R, Choyke PL. Improving conventional enhanced permeability and retention (EPR) effects; what is the appropriate target? Theranostics. 2014;4(1):81–9.

    Article  CAS  Google Scholar 

  27. Levy G. Pharmacological target-mediated drug disposition. Clin Pharmacol Ther. 1994;56(3):248–52.

    Article  CAS  PubMed  Google Scholar 

  28. Tabrizi M, Bornstein GG, Suria H. Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease. AAPS J. 2010;12(1):33–43.

    Article  CAS  PubMed  Google Scholar 

  29. Reuter KG et al. Targeted PRINT hydrogels: the role of nanoparticle size and ligand density on cell association, biodistribution, and tumor accumulation. Nano Lett. 2015;15(10):6371–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dua P, Hawkins E, van der Graaf PH. A tutorial on target-mediated drug disposition (TMDD) models. CPT Pharm Syst Pharmacol. 2015;4(6):324–37.

    Article  CAS  Google Scholar 

  31. Xie Y et al. Drug delivery to the lymphatic system: importance in future cancer diagnosis and therapies. Exp Opin Drug Deliv. 2009;6(8):785–92.

    Article  CAS  Google Scholar 

  32. Dukhin SS, Labib ME. Convective diffusion of nanoparticles from the epithelial barrier toward regional lymph nodes. Adv Colloid Inter Sci. 2013;199:23–43.

    Article  Google Scholar 

  33. Kwon K. Development of physiological pharmacokinetic model. Arch Pharm Res. 1987;10(4):250–7.

    Article  CAS  Google Scholar 

  34. Davda JP et al. A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs. Int Immunopharmacol. 2008;8(3):401–13.

    Article  CAS  PubMed  Google Scholar 

  35. Lin ZM, Monteiro-Riviere NA, Riviere JE. A physiologically based pharmacokinetic model for polyethylene glycol-coated gold nanoparticles of different sizes in adult mice. Nanotoxicology. 2016;10(2):162–72.

    CAS  PubMed  Google Scholar 

  36. Li D. et al. Using a PBPK model to study the influence of different characteristics of nanoparticles on their biodistribution. Nanosafe 2012: International Conferences on Safe Production and Use of Nanomaterials, 2013 p 429.

  37. Li D et al. Physiologically based pharmacokinetic modeling of polyethylene glycol-coated polyacrylamide nanoparticles in rats. Nanotoxicology. 2014;8 Suppl 1:128–37.

    Article  PubMed  Google Scholar 

  38. Hendriks BS et al. Multiscale kinetic modeling of liposomal Doxorubicin delivery quantifies the role of tumor and drug-specific parameters in local delivery to tumors. CPT Pharm Syst Pharmacol. 2012;1:e15.

    Article  CAS  Google Scholar 

  39. Sadauskas E et al. Protracted elimination of gold nanoparticles from mouse liver. Nanomed-Nanotechnol Biol Med. 2009;5(2):162–9.

    Article  CAS  Google Scholar 

  40. Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine. 2008;3(5):703–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Choi HS et al. Renal clearance of quantum dots. Nat Biotechnol. 2007;25(10):1165–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Almeida JP et al. In vivo biodistribution of nanoparticles. Nanomedicine (Lond). 2011;6(5):815–35.

    Article  CAS  Google Scholar 

  43. Semmler-Behnke M et al. Biodistribution of 1.4- and 18-nm gold particles in rats. Small. 2008;4(12):2108–11.

    Article  CAS  PubMed  Google Scholar 

  44. Lipka J et al. Biodistribution of PEG-modified gold nanoparticles following intratracheal instillation and intravenous injection. Biomaterials. 2010;31(25):6574–81.

    Article  CAS  PubMed  Google Scholar 

  45. Li S et al. Doxorubicin loaded pH-responsive micelles capable of rapid intracellular drug release for potential tumor therapy. J Biomed Nanotechnol. 2014;10(8):1480–9.

    Article  CAS  PubMed  Google Scholar 

  46. Dong D et al. Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112. Int J Nanomed. 2015;10:2521–35.

    CAS  Google Scholar 

  47. Lankveld DP et al. The kinetics of the tissue distribution of silver nanoparticles of different sizes. Biomaterials. 2010;31(32):8350–61.

    Article  CAS  PubMed  Google Scholar 

  48. Lin ZM et al. A computational framework for interspecies pharmacokinetics, exposure and toxicity assessment of gold nanoparticles. Nanomedicine. 2016;11(2):107–19.

    Article  CAS  PubMed  Google Scholar 

  49. Wenger Y et al. Tissue distribution and pharmacokinetics of stable polyacrylamide nanoparticles following intravenous injection in the rat. Toxicol Appl Pharmacol. 2011;251(3):181–90.

    Article  CAS  PubMed  Google Scholar 

  50. Gilkey MJ et al. Physiologically based pharmacokinetic modeling of fluorescently labeled block copolymer nanoparticles for controlled drug delivery in leukemia therapy. CPT Pharmacometrics Syst Pharmacol. 2015;4(3):e00013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Qin S et al. An imaging-driven model for liposomal stability and circulation. Mol Pharm. 2010;7(1):12–21.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hack CE. Bayesian analysis of physiologically based toxicokinetic and toxicodynamic models. Toxicology. 2006;221(2–3):241–8.

    Article  CAS  PubMed  Google Scholar 

  53. Moss DM, Siccardi M. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling. Br J Pharmacol. 2014;171(17):3963–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Moschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm. 2013;453(1):142–56.

    Article  PubMed  Google Scholar 

  55. Zou, P., Drug products containing nanomaterials: regulatory pathways and quality review. 2015, AAPS Webinar.

  56. US-EPA, Approaches for the application of physiologically based pharmacokinetic (PBPK) models and supporting data in risk assessment. 2006: Washington, DC.

  57. WHO, Characterization and application of physiologically based pharmacokinetic models in risk assessment. 2010: http://www.who.int/ipcs/methods/harmonization/areas/pbpk_models.pdf?ua=1.

  58. Thies RL et al. Method for rapid separation of liposome-associated doxorubicin from free doxorubicin in plasma. Anal Biochem. 1990;188(1):65–71.

    Article  CAS  PubMed  Google Scholar 

  59. Thode K et al. Determination of plasma protein adsorption on magnetic iron oxides: sample preparation. Pharm Res. 1997;14(7):905–10.

    Article  CAS  PubMed  Google Scholar 

  60. Gray EP et al. Extraction and analysis of silver and gold nanoparticles from biological tissues using single particle inductively coupled plasma mass spectrometry. Environ Sci Technol. 2013;47(24):14315–23.

    Article  CAS  PubMed  Google Scholar 

  61. Zamboni WC et al. Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models. J Liposome Res. 2011;21(1):70–80.

    Article  CAS  PubMed  Google Scholar 

  62. Zamboni WC et al. Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors. J Liposome Res. 2011;21(2):158–65.

    Article  CAS  PubMed  Google Scholar 

  63. La-Beck NM et al. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol. 2012;69(1):43–50.

    Article  CAS  PubMed  Google Scholar 

  64. Sahneh FD et al. Predicting the impact of biocorona formation kinetics on interspecies extrapolations of nanoparticle biodistribution modeling. Nanomedicine. 2015;10(1):25–33.

    Article  CAS  PubMed  Google Scholar 

  65. Caron WP et al. Translational studies of phenotypic probes for the mononuclear phagocyte system and liposomal pharmacology. J Pharmacol Exp Ther. 2013;347(3):599–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gabizon A et al. An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin. Cancer Chemother Pharmacol. 2008;61(4):695–702.

    Article  CAS  PubMed  Google Scholar 

  67. van Etten EW et al. Administration of liposomal agents and blood clearance capacity of the mononuclear phagocyte system. Antimicrob Agents Chemother. 1998;42(7):1677–81.

    PubMed  PubMed Central  Google Scholar 

  68. Saadati R et al. Accelerated blood clearance of PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, PEG coating, and encapsulated anticancer drug. Pharm Res. 2013;30(4):985–95.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Office of Pharmaceutical Quality, US Food and Drug Administration, Silver Spring, Maryland, USA

    Min Li, Katherine Tyner & Sau Lee

  2. Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland, USA

    Peng Zou

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  1. Min Li
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  2. Peng Zou
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Correspondence to Peng Zou.

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This article reflects the views of the authors and should not be construed to represent FDA’s views or policies. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services.

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Guest Editors: Katherine Tyner, Sau (Larry) Lee, and Marc Wolfgang

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Li, M., Zou, P., Tyner, K. et al. Physiologically Based Pharmacokinetic (PBPK) Modeling of Pharmaceutical Nanoparticles. AAPS J 19, 26–42 (2017). https://doi.org/10.1208/s12248-016-0010-3

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  • DOI: https://doi.org/10.1208/s12248-016-0010-3

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