Pharmaceutical Research

, Volume 27, Issue 5, pp 920–932 | Cite as

Interspecies Scaling of Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Type I Interferons

  • Leonid Kagan
  • Anson K. Abraham
  • John M. Harrold
  • Donald E. MagerEmail author
Research Paper



To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD).


PK and PD profiles of human IFN-β1a, IFN-β1b, and IFN-α2a in humans, monkeys, rats, and mice from nine studies were extracted from the literature by digitization. Concentration-time profiles from different species were fitted simultaneously using various allometric relationships to scale model-specific parameters.


PK/PD profiles of IFN-β1a in humans and monkeys were successfully characterized by utilizing the same rate constant parameters and scaling the volume of the central compartment to body weight using an allometric exponent of 1. Concentration and effect profiles of other IFNs were also well described by changing only the affinity of the drug to its receptor. PK profiles in rodents were simulated using an allometric exponent of −0.25 for the first-order elimination rate constant, and no receptor-binding was included given the lack of cross-reactivity.


An integrated TMDD PK/PD model was successfully combined with classic allometric scaling techniques and showed good predictive performance. Several parameters obtained from one IFN can be effectively shared to predict the kinetic behavior of other IFN subtypes.


allometry interferon nonlinear pharmacokinetics receptor binding target-mediated drug disposition 



This work was supported, in part, by Grant GM57980 from the National Institutes of Health (D.E.M.), the Center for Protein Therapeutics, University at Buffalo, SUNY (L.K. and J.M.H.), and the University at Buffalo—Pfizer Strategic Alliance (A.K.A.). Partial results of this study were presented in a poster at the 2009 AAPS Annual Meeting in Los Angeles, CA.


  1. 1.
    Bekisz J, Schmeisser H, Hernandez J, Goldman ND, Zoon KC. Human interferons alpha, beta and omega. Growth Factors. 2004;22:243–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Samarajiwa SA, Wilson W, Hertzog PJ, Interferons TI. Genetics and structure. In: Meager A, editor. The interferons: characterization and application. Weinheim: WILEY-VCH Verlag GmbH & Co. KGaA; 2006. p. 3–34.Google Scholar
  3. 3.
    Mogensen KE, Lewerenz M, Reboul J, Lutfalla G, Uze G. The type I interferon receptor: structure, function, and evolution of a family business. J Interferon Cytokine Res. 1999;19:1069–98.CrossRefPubMedGoogle Scholar
  4. 4.
    de Weerd NA, Samarajiwa SA, Hertzog PJ. Type I interferon receptors: biochemistry and biological functions. J Biol Chem. 2007;282:20053–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem. 1987;56:727–77.CrossRefPubMedGoogle Scholar
  6. 6.
    Fuchs D, Weiss G, Reibnegger G, Wachter H. The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases. Crit Rev Clin Lab Sci. 1992;29:307–41.CrossRefPubMedGoogle Scholar
  7. 7.
    Chiang J, Gloff CA, Soike KF, Williams G. Pharmacokinetics and antiviral activity of recombinant human interferon-beta ser17 in African green monkeys. J Interferon Res. 1993;13:111–20.PubMedGoogle Scholar
  8. 8.
    Mager DE, Neuteboom B, Efthymiopoulos C, Munafo A, Jusko WJ. Receptor-mediated pharmacokinetics and pharmacodynamics of interferon-beta1a in monkeys. J Pharmacol Exp Ther. 2003;306:262–70.CrossRefPubMedGoogle Scholar
  9. 9.
    Levy G. Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther. 1994;56:248–52.CrossRefPubMedGoogle Scholar
  10. 10.
    Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28:507–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Mager DE. Target-mediated drug disposition and dynamics. Biochem Pharmacol. 2006;72:1–10.CrossRefPubMedGoogle Scholar
  12. 12.
    Mager DE, Jusko WJ. Receptor-mediated pharmacokinetic/pharmacodynamic model of interferon-β 1a in humans. Pharm Res. 2002;19:1537–43.CrossRefPubMedGoogle Scholar
  13. 13.
    Segrave AM, Mager DE, Charman SA, Edwards GA, Porter CJ. Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep. J Pharmacol Exp Ther. 2004;309:1085–92.CrossRefPubMedGoogle Scholar
  14. 14.
    Woo S, Krzyzanski W, Jusko WJ. Target-mediated pharmacokinetic and pharmacodynamic model of recombinant human erythropoietin (rHuEPO). J Pharmacokinet Pharmacodyn. 2007;34:849–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Adolph EF. Quantitative relations in the physiological constitutions of mammals. Science. 1949;109:579–85.CrossRefPubMedGoogle Scholar
  16. 16.
    Boxenbaum H, Ronfeld R. Interspecies pharmacokinetic scaling and the Dedrick plots. Am J Physiol. 1983;245:R768–775.PubMedGoogle Scholar
  17. 17.
    Dedrick RL. Animal scale-up. J Pharmacokinet Biopharm. 1973;1:435–61.CrossRefPubMedGoogle Scholar
  18. 18.
    Tang H, Mayersohn M. A novel model for prediction of human drug clearance by allometric scaling. Drug Metab Dispos. 2005;33:1297–303.CrossRefPubMedGoogle Scholar
  19. 19.
    Mordenti J, Chen SA, Moore JA, Ferraiolo BL, Green JD. Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm Res. 1991;8:1351–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Mahmood I. Interspecies scaling of protein drugs: prediction of clearance from animals to humans. J Pharm Sci. 2004;93:177–85.CrossRefPubMedGoogle Scholar
  21. 21.
    Tang H, Mayersohn M. A global examination of allometric scaling for predicting human drug clearance and the prediction of large vertical allometry. J Pharm Sci. 2006;95:1783–99.CrossRefPubMedGoogle Scholar
  22. 22.
    Woo S, Jusko WJ. Interspecies comparisons of pharmacokinetics and pharmacodynamics of recombinant human erythropoietin. Drug Metab Dispos. 2007;35:1672–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Buchwalder PA, Buclin T, Trinchard I, Munafo A, Biollaz J. Pharmacokinetics and pharmacodynamics of IFN-beta 1a in healthy volunteers. J Interferon Cytokine Res. 2000;20:857–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Mager DE, Krzyzanski W. Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res. 2005;22:1589–96.CrossRefPubMedGoogle Scholar
  25. 25.
    Kushnaryov VM, MacDonald HS, Sedmak JJ, Grossberg SE. Murine interferon-beta receptor-mediated endocytosis and nuclear membrane binding. Proc Natl Acad Sci U S A. 1985;82:3281–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Bino T, Edery H, Gertler A, Rosenberg H. Involvement of the kidney in catabolism of human leukocyte interferon. J Gen Virol. 1982;59:39–45.CrossRefPubMedGoogle Scholar
  27. 27.
    Bino T, Madar Z, Gertler A, Rosenberg H. The kidney is the main site of interferon degradation. J Interferon Res. 1982;2:301–8.PubMedGoogle Scholar
  28. 28.
    Rosenberg H, Madar Z, Gertler A, Rubinstein M, Bino T. The fate of [125I]-labeled human leukocyte-derived alpha interferon in the rat. J Interferon Res. 1985;5:121–7.PubMedGoogle Scholar
  29. 29.
    Interferon: The 50th Anniversary, Springer-Verlag, Berlin, 2007.Google Scholar
  30. 30.
    Sharma A, Ebling WF, Jusko WJ. Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena. J Pharm Sci. 1998;87:1577–84.CrossRefPubMedGoogle Scholar
  31. 31.
    Mager DE, Jusko WJ. Pharmacodynamic modeling of time-dependent transduction systems. Clin Pharmacol Ther. 2001;70:210–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Chiang J, Gloff CA, Yoshizawa CN, Williams GJ. Pharmacokinetics of recombinant human interferon-beta ser in healthy volunteers and its effect on serum neopterin. Pharm Res. 1993;10:567–72.CrossRefPubMedGoogle Scholar
  33. 33.
    Mager DE, Jusko WJ. Development of translational pharmacokinetic-pharmacodynamic models. Clin Pharmacol Ther. 2008;83:909–12.CrossRefPubMedGoogle Scholar
  34. 34.
    Mager DE, Woo S, Jusko WJ. Scaling pharmacodynamics from in vitro and preclinical animal studies to humans. Drug Metab Pharmacokinet. 2009;24:16–24.CrossRefPubMedGoogle Scholar
  35. 35.
    Cosson VF, Fuseau E, Efthymiopoulos C, Bye A. Mixed effect modeling of sumatriptan pharmacokinetics during drug development. I: Interspecies allometric scaling. J Pharmacokinet Biopharm. 1997;25:149–67.CrossRefPubMedGoogle Scholar
  36. 36.
    Jolling K, Perez Ruixo JJ, Hemeryck A, Vermeulen A, Greway T. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin. Eur J Pharm Sci. 2005;24:465–75.CrossRefPubMedGoogle Scholar
  37. 37.
    Gloff C, Wills R. Pharmacokinetics and metabolism of therapeutic cytokines. New York: Plenum; 1992.Google Scholar
  38. 38.
    McKenna SD, Vergilis K, Arulanandam AR, Weiser WY, Nabioullin R, Tepper MA. Formation of human IFN-beta complex with the soluble type I interferon receptor IFNAR-2 leads to enhanced IFN stability, pharmacokinetics, and antitumor activity in xenografted SCID mice. J Interferon Cytokine Res. 2004;24:119–29.CrossRefPubMedGoogle Scholar
  39. 39.
    Pepinsky RB, LePage DJ, Gill A, Chakraborty A, Vaidyanathan S, Green M, et al. Improved pharmacokinetic properties of a polyethylene glycol-modified form of interferon-beta-1a with preserved in vitro bioactivity. J Pharmacol Exp Ther. 2001;297:1059–66.PubMedGoogle Scholar
  40. 40.
    Wills RJ, Dennis S, Spiegel HE, Gibson DM, Nadler PI. Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection. Clin Pharmacol Ther. 1984;35:722–7.PubMedGoogle Scholar
  41. 41.
    Wills RJ, Spiegel HE, Soike KF. Pharmacokinetics of recombinant alpha A interferon following I.V. infusion and bolus, I.M., and P.O. administrations to African green monkeys. J Interferon Res. 1984;4:399–409.PubMedGoogle Scholar
  42. 42.
    Lave T, Levet-Trafit B, Schmitt-Hoffmann AH, Morgenroth B, Richter W, Chou RC. Interspecies scaling of interferon disposition and comparison of allometric scaling with concentration-time transformations. J Pharm Sci. 1995;84:1285–90.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Leonid Kagan
    • 1
  • Anson K. Abraham
    • 1
  • John M. Harrold
    • 1
  • Donald E. Mager
    • 1
    • 2
    Email author
  1. 1.Department of Pharmaceutical Sciences, University at BuffaloState University of New YorkAmherstUSA
  2. 2.Department of Pharmaceutical Sciences, University at BuffaloSUNYBuffaloUSA

Personalised recommendations