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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
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.
Zhao P et al. Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review. Clin Pharmacol Ther. 2011;89(2):259–67.
Li M et al. Physiologically based pharmacokinetic modeling of nanoparticles. ACS Nano. 2010;4(11):6303–17.
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.
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.
Li M et al. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content. Int J Nanomed. 2012;7:1345–56.
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.
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.
Lin P et al. Computational and ultrastructural toxicology of a nanoparticle, quantum dot 705, in mice. Environ Sci Technol. 2008;42(16):6264–70.
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.
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.
Kagan L et al. Dual physiologically based pharmacokinetic model of liposomal and nonliposomal amphotericin B disposition. Pharm Res. 2014;31(1):35–45.
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.
Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 2005;113(7):823–39.
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.
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.
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.
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.
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.
Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.
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.
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.
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.
Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33(9):941–51.
Mahmoudi M et al. Protein-nanoparticle interactions: opportunities and challenges. Chem Rev. 2011;111(9):5610–37.
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.
Levy G. Pharmacological target-mediated drug disposition. Clin Pharmacol Ther. 1994;56(3):248–52.
Tabrizi M, Bornstein GG, Suria H. Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease. AAPS J. 2010;12(1):33–43.
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.
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.
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.
Dukhin SS, Labib ME. Convective diffusion of nanoparticles from the epithelial barrier toward regional lymph nodes. Adv Colloid Inter Sci. 2013;199:23–43.
Kwon K. Development of physiological pharmacokinetic model. Arch Pharm Res. 1987;10(4):250–7.
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.
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.
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.
Li D et al. Physiologically based pharmacokinetic modeling of polyethylene glycol-coated polyacrylamide nanoparticles in rats. Nanotoxicology. 2014;8 Suppl 1:128–37.
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.
Sadauskas E et al. Protracted elimination of gold nanoparticles from mouse liver. Nanomed-Nanotechnol Biol Med. 2009;5(2):162–9.
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.
Choi HS et al. Renal clearance of quantum dots. Nat Biotechnol. 2007;25(10):1165–70.
Almeida JP et al. In vivo biodistribution of nanoparticles. Nanomedicine (Lond). 2011;6(5):815–35.
Semmler-Behnke M et al. Biodistribution of 1.4- and 18-nm gold particles in rats. Small. 2008;4(12):2108–11.
Lipka J et al. Biodistribution of PEG-modified gold nanoparticles following intratracheal instillation and intravenous injection. Biomaterials. 2010;31(25):6574–81.
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.
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.
Lankveld DP et al. The kinetics of the tissue distribution of silver nanoparticles of different sizes. Biomaterials. 2010;31(32):8350–61.
Lin ZM et al. A computational framework for interspecies pharmacokinetics, exposure and toxicity assessment of gold nanoparticles. Nanomedicine. 2016;11(2):107–19.
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.
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.
Qin S et al. An imaging-driven model for liposomal stability and circulation. Mol Pharm. 2010;7(1):12–21.
Hack CE. Bayesian analysis of physiologically based toxicokinetic and toxicodynamic models. Toxicology. 2006;221(2–3):241–8.
Moss DM, Siccardi M. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling. Br J Pharmacol. 2014;171(17):3963–79.
Moschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm. 2013;453(1):142–56.
Zou, P., Drug products containing nanomaterials: regulatory pathways and quality review. 2015, AAPS Webinar.
US-EPA, Approaches for the application of physiologically based pharmacokinetic (PBPK) models and supporting data in risk assessment. 2006: Washington, DC.
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.
Thies RL et al. Method for rapid separation of liposome-associated doxorubicin from free doxorubicin in plasma. Anal Biochem. 1990;188(1):65–71.
Thode K et al. Determination of plasma protein adsorption on magnetic iron oxides: sample preparation. Pharm Res. 1997;14(7):905–10.
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.
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.
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.
La-Beck NM et al. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol. 2012;69(1):43–50.
Sahneh FD et al. Predicting the impact of biocorona formation kinetics on interspecies extrapolations of nanoparticle biodistribution modeling. Nanomedicine. 2015;10(1):25–33.
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.
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.
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.
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.
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.
Guest Editors: Katherine Tyner, Sau (Larry) Lee, and Marc Wolfgang
About this article
Cite this article
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
- model extrapolation
- MPS uptake
- PBPK modeling