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Pharmaceutical Research

, Volume 19, Issue 10, pp 1537–1543 | Cite as

Receptor-Mediated Pharmacokinetic/Pharmacodynamic Model of Interferon-β 1a in Humans

  • Donald E. Mager
  • William J. JuskoEmail author
Article

Abstract

Purpose. An integrated receptor-based pharmacokinetic/pharmaco- dynamic (PK/PD) model of interferon-β 1a (IFN-β 1a) previously developed for monkeys was used to capture the time-course of drug and induced neopterin concentrations after intravenous (IV) and subcutaneous (SC) dosing in humans.

Methods. Data were extracted from the literature by digitalization. Single-dose (3 IV doses and 1 SC dose) PK/PD profiles were simultaneously fitted using the basic model and the ADAPT II computer program. Additional submodels incorporating neutralizing antibody formation and negative feedback inhibition were applied to account for drug accumulation and lower than expected neopterin concentrations encountered after multiple-dosing (1 SC dose every 48 hs).

Results. The basic model jointly-captured the nonlinear PK behavior of the drug and induced neopterin concentrations after all single doses. Slow and incomplete absorption (F = 0.33) of the SC dose resulted in prolonged drug concentrations reflective of flip-flop kinetics. Despite lower drug concentrations, SC dosing produced a similar neopterin profile as compared with the IV doses; however, with a longer time to peak effect and slightly higher neopterin concentrations at later time points. The PD component of the model represents a modified precursor-dependent indirect response model driven by the amount of internalized drug-receptor complex. The latter stimulated a 6-fold increase in the production of the neopterin precursor (Smax = 5.89). Drug accumulation and lower than expected neopterin concentrations after multiple dosing were also captured after the inclusion of the submodels.

Conclusions. The present integrated PK/PD model for IFN-β 1a is mechanistic in nature with receptor-mediated disposition and dynamics and was successfully applied to human clinical data.

interferon-beta pharmacokinetics pharmacodynamics mathematical modeling humans 

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REFERENCES

  1. 1.
    J. H. Noseworthy, C. Lucchinetti, M. Rodriguez, and B. G. Weinshenker. Multiple sclerosis. N.Engl.J.Med. 343:938-952 (2000).Google Scholar
  2. 2.
    W. Leonard. Type I cytokines and interferons and their receptors. In W. Paul (ed.), Fundamental Immunology, Lippincott-Raven, Philadelphia, Pennsylvania, 1999 pp. 741-774.Google Scholar
  3. 3.
    S. Pestka, J. A. Langer, K. C. Zoon, and C. E. Samuel. Interferons and their actions. Annu.Rev.Biochem. 56:727-777 (1987).Google Scholar
  4. 4.
    J. Alam, S. Goelz, P. Rioux, J. Scaramucci, W. Jones, A. McAllister, M. Campion, and M. Rogge. Comparative pharmacokinetics and pharmacodynamics of two recombinant human interferon beta-1a (IFN beta-1 a) products administered intramuscularly in healthy male and female volunteers. Pharm.Res. 14:546-549 (1997).Google Scholar
  5. 5.
    J. Chiang, C. A. Gloff, C. N. Yoshizawa, and G. J. Williams. Pharmacokinetics of recombinant human interferon-beta ser in healthy volunteers and its effect on serum neopterin. Pharm.Res. 10:567-572 (1993).Google Scholar
  6. 6.
    G. Fierlbeck, A. Ulmer, T. Schreiner, W. Stroebel, U. Schiebel, and J. Brzoska. Pharmacodynamics of recombinant IFN-beta during long-term treatment of malignant melanoma. J.Interferon Cytokine Res. 16:777-781 (1996).Google Scholar
  7. 7.
    L. E. Rothuizen, T. Buclin, F. Spertini, I. Trinchard, A. Munafo, P. A. Buchwalder, A. Ythier, and J. Biollaz. Influence of interferon beta-1a dose frequency on PBMC cytokine secretion and biologic effect markers. J.Neuroimmunology 99:131-141 (1999).Google Scholar
  8. 8.
    P. Salmon, J. Y. Le Cotonnec, A. Galazka, A. Abdul-Ahad, and A. Darragh. Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers. J.Interferon Cytokine Res. 16:759-764 (1996).Google Scholar
  9. 9.
    D. E. Mager, B. Neuteboom, A. Murafo, C. Efthymiopoulos, and W. J. Jusko. Receptor-mediated pharmacokinetics and pharmacodynamics of IFN-beta 1a following intravenous and subcutaneous dosing in monkeys. In Pharmaceutical Congress of the Americas. AAPS, Orlando, Florida, 2001.Google Scholar
  10. 10.
    D. E. Mager and W. J. Jusko. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J.Pharmacokinet.Pharmacodyn. 28:507-532 (2001).Google Scholar
  11. 11.
    P. A. Buchwalder, T. Buclin, I. Trinchard, A. Munafo, and J. Biollaz. Pharmacokinetics and pharmacodynamics of IFN-beta 1a in healthy volunteers. J.Interferon Cytokine Res. 20:857-866 (2000).Google Scholar
  12. 12.
    K. C. Zoon and H. Arnheiter. Studies of the interferon receptors. Pharmacol.Ther. 24:259-278 (1984).Google Scholar
  13. 13.
    E. Radwanski, A. Chakraborty, S. Van Wart, R. D. Huhn, D. L. Cutler, M. B. Affrime, and W. J. Jusko. Pharmacokinetics and leukocyte responses of recombinant human interleukin-10. Pharm.Res. 15:1895-1901 (1998).Google Scholar
  14. 14.
    A. Supersaxo, W. Hein, and H. Steffen. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm.Res. 7:167-169 (1990).Google Scholar
  15. 15.
    D. Fuchs, G. Weiss, G. Reibnegger, and H. Wachter. The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases. Crit.Rev.Clin.Lab.Sci. 29:307-341 (1992).Google Scholar
  16. 16.
    A. Sharma, W. F. Ebling, and W. J. Jusko. Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena. J.Pharm.Sci. 87:1577-1584 (1998).Google Scholar
  17. 17.
    R. Braeckman. Pharmacokinetics and pharmacodynamics of protein therapeutics. In R. E. Reid (ed.), Peptide and Protein Drug Analysis, University of British Columbia, Vancouver, 1999 pp. 633-669.Google Scholar
  18. 18.
    N. L. Dayneka, V. Garg, and W. J. Jusko. Comparison of four basic models of indirect pharmacodynamic responses. J.Pharmacokinet.Biopharm. 21:457-478 (1993).Google Scholar
  19. 19.
    H. Cheng, A. Staubus, and L. Shum. An area function method for estimating the apparent absorption rate constant. Pharm.Res. 5:57-60 (1988).Google Scholar
  20. 20.
    D. Z. D'Argenio and A. Schumitzky. ADAPT II user's guide. Biomedical Simulations Resource, Los Angeles, California, 1997.Google Scholar
  21. 21.
    S. D. Cook, J. R. Quinless, A. Jotkowitz, P. Beaton, and the Neutralizing Antibody Study Group. Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients. Neurology 57:1080-1084 (2001).Google Scholar
  22. 22.
    Y. Sugiyama and M. Hanano. Receptor-mediated transport of peptide hormones and its importance in the overall hormone disposition in the body. Pharm.Res. 6:192-202 (1989).Google Scholar
  23. 23.
    G. Levy. Pharmacologic target-mediated drug disposition. Clin.Pharmacol.Ther. 56:248-252 (1994).Google Scholar
  24. 24.
    G. Stark, I. Kerr, B. Williams, R. Silverman, and R. Schreiber. How cells respond to interferons. Annu.Rev.Biochem. 67:227-264 (1998).Google Scholar
  25. 25.
    A. M. Liberati, M. Fizzotti, M. G. Proietti, R. Di Marzio, M. Schippa, B. Biscottini, M. Senatore, P. Berruto, S. Canali, G. Peretti, and G. Zanolo. Biochemical host response to interferonbeta. J.Interferon Res. 8:765-777 (1988).Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffalo

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