Journal of Pharmacokinetics and Pharmacodynamics

, Volume 28, Issue 6, pp 507–532 | Cite as

General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition

  • Donald E. Mager
  • William J. Jusko


Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent Vss and CLD decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-β 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.

target-mediated drug disposition nonlinear pharmacokinetics imirestat bosentan interferon-β receptor binding receptor-mediated endocytosis mathematical modeling human 


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  1. 1.
    G. Levy. Pharmacologic target-mediated drug disposition. Clin. Pharmacol. Ther. 56:248–252 (1994).Google Scholar
  2. 2.
    A. E. Till, H. J. Gomez, M. Hichens, J. A. Bolognese, W. R. McNabb, B. A. Brooks, F. Noormohamed, and A. F. Lant. Pharmacokinetics of repeated single oral doses of enalapril maleate (MK-421) in normal volunteers. Biopharm. Drug Dispos. 5:273–280 (1984).Google Scholar
  3. 3.
    K. R. Lees, A. W. Kelman, J. L. Reid, and B. Whiting. Pharmacokinetics of an ACE inhibitor, S-9780, in man: evidence of tissue binding. J. Pharmacokinet. Biopharm. 17:529–550 (1989).Google Scholar
  4. 4.
    R. J. MacFadyen, K. R. Lees, and J. L. Reid. Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normotensive male volunteers. Br. J. Clin. Pharmacol. 34:115-121 (1992).Google Scholar
  5. 5.
    R. Klausner, J. V. Renswoude, J. Harford, C. Wofsy, and B. Goldstein. Mathematical modeling of receptor-mediated endocytosis. In I. Pastan and M. C. Willingham (eds.), Endocytosis, Plenum Press, New York, 1985, pp. 259–279.Google Scholar
  6. 6.
    V. L. Shepherd. Intracellular pathways and mechanisms of sorting in receptor-mediated endocytosis. Trends Pharmacol. Sci. 10:458–462 (1989).Google Scholar
  7. 7.
    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
  8. 8.
    M. S. Brown, R. G. Anderson, and J. L. Goldstein. Recycling receptors: the round-trip itinerary of migrant membrane proteins. Cell. 32:663–667 (1983).Google Scholar
  9. 9.
    I. Pastan and M. C. Willingham. The pathway of endocytosis. In I. Pastan and M. C. Willingham (eds.), Endocytosis, Plenum Press, New York, 1985, pp. 1–44.Google Scholar
  10. 10.
    J. E. Rothman and F. T. Wieland. Protein sorting by transport vesicles. Science. 272:227–234 (1996).Google Scholar
  11. 11.
    M. Blick, S. A. Sherwin, M. Rosenblum, and J. Gutterman. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res. 47:2986–2989 (1987).Google Scholar
  12. 12.
    D. Z. D'Argenio and A. Schumitzky. ADAPT II user's guide. Biomedical Simulations Resource, Los Angeles (1997).Google Scholar
  13. 13.
    M. Gibaldi and D. Perrier. Pharmacokinetics, Marcel Dekker, Inc., New York, 1982.Google Scholar
  14. 14.
    P. Veng-Pedersen and W. R. Gillespie. Single pass mean residence time in peripheral tissues: a distribution parameter intrinsic to the tissue affinity of a drug. J. Pharm. Sci. 75:1119–1126 (1986).Google Scholar
  15. 15.
    R. Brazzell, P. Mayer, R. Dobbs, P. McNamara, R. Teng, and J. Slattery. Dose-dependent pharmacokinetics of the aldose reductase inhibitor imirestat in man. Pharm. Res. 8:112–118 (1991).Google Scholar
  16. 16.
    C. Weber, R. Schmitt, H. Birnboeck, G. Hopfgartner, S. van Marle, P. Peeters, J. Jonkman, and C. Jones. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin. Pharmacol. Ther. 60:124–137 (1996).Google Scholar
  17. 17.
    P. A. Buchwalder, T. Buclin, I. Trinchard, A. Munafo, and J. Biollaz. Pharmacokinetics and pharmacodynamics of IFN-β1a in healthy volunteers. J. Interferon Cytokine Res. 20:857–866 (2000).Google Scholar
  18. 18.
    S. Oie, T. W. Guentert, and T. N. Tozer. Effect of saturable binding on the pharmacokinetics of drugs: a simulation. J. Pharm. Pharmacol. 32:471–477 (1980).Google Scholar
  19. 19.
    J. H. Lin. Dose-dependent pharmacokinetics: experimental observations and theoretical considerations. Biopharm. Drug Dispos. 15:1–31 (1994).Google Scholar
  20. 20.
    W. J. Jusko. Guidelines for collection and analysis of pharmacokinetic data. In W. E. Evans, J. J. Schentag, and W. J. Jusko (eds.), Applied Pharmacokinetics, Applied Therapeutics, Inc., Vancouver, 1992, Ch. 2.Google Scholar
  21. 21.
    J. G. Wagner. A new generalized nonlinear pharmacokinetic model and its implications. In J. G. Wagner (ed.), Biopharmaceutics and Relevant Pharmacokinetics, Drug Intelligence Publications, Hamilton, 1971, pp. 302–317.Google Scholar
  22. 22.
    H. Y. Cheng and W. J. Jusko. Mean residence time concepts for pharmacokinetic systems with nonlinear drug elimination described by the Michaelis–Menten equation. Pharm. Res. 5:156–164 (1988).Google Scholar
  23. 23.
    J. Y. Chien, C. R. Banfield, R. K. Brazzell, P. R. Mayer, and J. T. Slattery. Saturable tissue binding and imirestat pharmacokinetics in rats. Pharm. Res. 9:469–973 (1992).Google Scholar
  24. 24.
    M. Clozel. Endothelin receptor antagonists: current status and perspectives. J. Cardioû asc. Pharmacol. 35:S65–S68 (2000).Google Scholar
  25. 25.
    M. Clozel et al., Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J. Pharmacol. Exp. Ther. 270:228–235 (1994).Google Scholar
  26. 26.
    C. Weber, R. Gasser, and G. Hopfgartner. Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects. Drug Metab. Dispos. 27:810–815 (1999).Google Scholar
  27. 27.
    C. Weber, R. Schmitt, H. Birnboeck, G. Hopfgartner, H. Eggers, J. Meyer, S. van Marle, H. W. Viischer, and J. H. Jonkman. Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers. J. Clin. Pharmacol. 39:703–714 (1999).Google Scholar
  28. 28.
    J. H. Noseworthy, C. Lucchinetti, M. Rodriguez, and B. G. Weinshenker. Multiple Sclerosis. NEJM 343:938–952 (2000).Google Scholar
  29. 29.
    J. Chiang, C. A. Gloff, C. N. Yoshizawa, and G. J. Williams. Pharmacokinetics of recombinant human interferon-βser in healthy volunteers and its effect on serum neopterin. Pharm. Res. 10:567–572 (1993).Google Scholar
  30. 30.
    P. Salmon, J. Y. Le Cotonnec, A. Galazka, A. Abdul-Ahad, and A. Darragh. Pharmacokinetics and pharmacodynamics of recombinant human interferon-βin healthy male volunteers. J. Interferon Cytokine Res. 16:759–764 (1996).Google Scholar
  31. 31.
    R. Wills. Clinical pharmacokinetics of interferons. Clin. Pharmacokinet. 19:390–399 (1990).Google Scholar
  32. 32.
    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-β1a (IFN-β1a) products administered intramuscularly in healthy male and female volunteers. Pharm. Res. 14:546–549 (1997).Google Scholar
  33. 33.
    C. Gloff and R. Wills. Pharmacokinetics and metabolism of therapeutic cytokines. In B. Ferraiolo, M. Mohler, and C. Gloff, (eds.), Protein Pharmacokinetics and Metabolism, Plenum Press, New York, 1992, pp. 127–150.Google Scholar
  34. 34.
    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
  35. 35.
    F. M. Gengo, J. J. Schentag, and W. J. Jusko. Pharmacokinetics of capacity-limited tissue distribution of methicillin in rabbits. J. Pharm. Sci. 73:867–873 (1984).Google Scholar
  36. 36.
    E. Snoeck, P. Jacqmin, A. Peer, and M. Danhof. A combined specific target site binding and pharmacokinetic model to explore the non-linear disposition of draflazine. J. Pharmacokinet. Biopharm. 27:257–280 (1999).Google Scholar
  37. 37.
    L. Gianni, C. M. Kearns, A. Giani, G. Capri, L. Vigano, A. Lacatelli, G. Bonadonna, and M. J. Egorin. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamic relationships in humans. J. Clin. Oncol. 13:180–190 (1995).Google Scholar
  38. 38.
    J. W. Black and P. Leff. Operational models of pharmacological agonism. Proc. R. Soc. Lond. B. Biol. Sci. 220:141–162 (1983).Google Scholar
  39. 39.
    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
  40. 40.
    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
  41. 41.
    Y. N. Sun and W. J. Jusko. Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics. J. Pharm. Sci. 87:732–737 (1998).Google Scholar
  42. 42.
    D. E. Mager and W. J. Jusko. Pharmacodynamic modeling of time-dependent transduction systems. Clin. Pharmacol. Ther. 70:210–216 (2001).Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Donald E. Mager
    • 1
  • William J. Jusko
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffalo

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