Pharmaceutical Research

, 26:2543 | Cite as

Physiologically-Based PK/PD Modelling of Therapeutic Macromolecules

  • Peter Thygesen
  • Panos Macheras
  • Achiel Van Peer
Expert Review


Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

Key Words

convective distribution cyclosporin A erythropoietin interspecies scaling macromolecules monoclonal antibodies natural cell lifespan concept neonatal Fc receptors non-linear pharmacokinetics permeability-limited distribution physiologically-based pharmacokinetic modelling PK/PD modelling target-mediated drug disposition 


  1. 1.
    Baumann A. Early development of therapeutic biologics— Pharmacokinetics. Curent Drug Metabolism. 2006;7:15–21.CrossRefGoogle Scholar
  2. 2.
    Kamiya H, Akita H, Harashima H. Pharmacokinetic and pharmacodynamic considerations in gene therapy. Drug Discov Today. 2003;8:990–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Tang L, Persky AM, Hochhaus G, Meibohm B. Pharmacokinetic aspects of biotechnology products. J Pharm Sci. 2004;93:2184–204.CrossRefPubMedGoogle Scholar
  4. 4.
    Rowland M, Balant L, Peck C. Physiologically based pharmacokinetics in drug development and regulatory science: a workshop report (Georgetown University, Washington, DC, May 29–30, 2002). AAPS J. 2004;6:56–67.PubMedGoogle Scholar
  5. 5.
    Edginton AN, Theil FP, Schmitt W, Willmann S. Whole body physiologically-based pharmacokinetic models: their use in clinical drug development. Expert Opin Drug Metab Toxicol. 2008;4:1143–52.CrossRefPubMedGoogle Scholar
  6. 6.
    Nestorov I. Whole-body physiologically based pharmacokinetic models. Expert Opin Drug Metab Toxicol. 2007;3:235–49.CrossRefPubMedGoogle Scholar
  7. 7.
    Kawai R, Mathew D, Tanaka C, Rowland M. Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human. J Pharmacol Exp Ther. 1998;287:457–68.PubMedGoogle Scholar
  8. 8.
    Tanaka C, Kawai R, Rowland M. Physiologically based pharmacokinetics of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats. J Pharmacokinet Biopharm. 1999;27:597–623.CrossRefPubMedGoogle Scholar
  9. 9.
    Willmann S, Schmitt W, Keldenich J, Dressman JB. A physiologic model for simulating gastrointestinal flow and drug absorption in rats. Pharm Res. 2003;20:1766–71.CrossRefPubMedGoogle Scholar
  10. 10.
    Willmann S, Lippert J, Schmitt W. From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools. Expert Opin Drug Metab Toxicol. 2005;1:159–68.CrossRefPubMedGoogle Scholar
  11. 11.
    von Kleist M, Huisinga W. Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution. J Pharmacokinet Pharmacodyn. 2007;34:789.CrossRefGoogle Scholar
  12. 12.
    Kawai R, Lemaire M, Steimer JL, Bruelisauer A, Niederberger W, Rowland M. Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125. J Pharmacokinet Biopharm. 1994;22:327–65.CrossRefPubMedGoogle Scholar
  13. 13.
    Garg A, Balthasar JP. Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn. 2007;34:687–709.CrossRefPubMedGoogle Scholar
  14. 14.
    Tanaka C, Kawai R, Rowland M. Dose-dependent pharmacokinetics of cyclosporin A in rats: events in tissues. Drug Metab Dispos. 2000;28:582–9.PubMedGoogle Scholar
  15. 15.
    Schmitt W, Willmann S. Physiology-based pharmacokinetic modelling: ready to be used. Drug Discovery Today: Technologies. 2004;1:449–55.CrossRefGoogle Scholar
  16. 16.
    Parrott N, Paquereau N, Coassolo P, Lave T. An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery. J Pharm Sci. 2005;94:2327–43.CrossRefPubMedGoogle Scholar
  17. 17.
    Parrott N, Jones H, Paquereau N, Lave T. Application of full physiological models for pharmaceutical drug candidate selection and extrapolation of pharmacokinetics to man. Basic Clin Pharmacol Toxicol. 2005;96:193–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Willmann S, Hohn K, Edginton A, Sevestre M, Solodenko J, Weiss W, et al. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn. 2007;34:401–31.CrossRefPubMedGoogle Scholar
  19. 19.
    Yu LX, Amidon GLA. Compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm. 1999;186:119–25.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmakokinetics and pharmacodynamics. Clin Pharmacol Ther 2008;1–11.Google Scholar
  21. 21.
    Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93:2645–68.CrossRefPubMedGoogle Scholar
  22. 22.
    Pelkonen O, Kapitulnik J, Gundert-Remy U, Boobis AR, Stockis A. Local kinetics and dynamics of xenobiotics. Crit Rev Toxicol. 2008;38:697–720.CrossRefPubMedGoogle Scholar
  23. 23.
    Mahmood I, Green MD. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin Pharmacokinet. 2005;44:331–47.CrossRefPubMedGoogle Scholar
  24. 24.
    Covell DG, Barbet J, Holton OD, Black CD, Parker RJ, Weinstein JN. Pharmacokinetics of monoclonal immunoglobulin G1, F(ab’)2, and Fab’ in mice. Cancer Res. 1986;46:3969–78.PubMedGoogle Scholar
  25. 25.
    Baxter LT, Zhu H, Mackensen DG, Jain RK. Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Res. 1994;54:1517–28.PubMedGoogle Scholar
  26. 26.
    Ferl GZ, Wu AM, DiStefano JJ III. A pedictive model of therapeutic monoclonal antibody dynamics and regulation by the neonatal Fc receptor (FcRn). Annals of Biomedical Engineering. 2005;33:1640–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Hansen RJ, Balthasar JP. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb Haemost. 2002;88:898–9.PubMedGoogle Scholar
  28. 28.
    Boxenbaum H. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J Pharmacokinet Biopharm. 1982;10:201–27.CrossRefPubMedGoogle Scholar
  29. 29.
    D’Souza RW, Boxenbaum H. Physiological pharmacokinetic models: some aspects of theory, practice and potential. Toxicol Ind Health. 1988;4:151–71.PubMedGoogle Scholar
  30. 30.
    Mahmood I. Application of fixed exponent 0.75 to the prediction of human drug clearance: an inaccurate and misleading concept. Drug Metabol Drug Interact. 2009;24:57–81.PubMedGoogle Scholar
  31. 31.
    Grene-Lerouge NA, Bazin-Redureau MI, Debray M, Scherrmann JM. Interspecies scaling of clearance and volume of distribution for digoxin-specific Fab. Toxicol Appl Pharmacol. 1996;138:84–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Woo S, Jusko WJ. Interspecies comparisons of pharmacokinetics and pharmacodynamics of recombinant human erythropoietin. Drug Metab Dispos. 2007;35:1672–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Vugmeyster Y, Szklut P, Tchistiakova L, Abraham W, Kasaian M, Xu X. Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of humanized monoclonal anti-IL-13 antibodies with different IL-13 neutralization mechanisms. Int Immunopharmacol. 2008;8:477–83.CrossRefPubMedGoogle Scholar
  34. 34.
    Krzyzanski W, Jusko WJ, Wacholtz MC, Minton N, Cheung WK. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects. Eur J Pharm Sci. 2005;26:295–306.CrossRefPubMedGoogle Scholar
  35. 35.
    Ramakrishnan R, Cheung WK, Wacholtz MC, Minton N, Jusko WJ. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers. J Clin Pharmacol. 2004;44:991–1002.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Peter Thygesen
    • 1
  • Panos Macheras
    • 2
  • Achiel Van Peer
    • 3
  1. 1.Exploratory ADME, Novo Nordisk A/SMåløvDenmark
  2. 2.Laboratory of Biopharmaceutics and Pharmacokinetics, School of PharmacyUniversity of AthensAthensGreece
  3. 3.Clinical Pharmacokinetics, Johnson and JohnsonBeerseBelgium

Personalised recommendations