Skip to main content

Advertisement

Springer Nature Link
Log in

General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition

  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. G. Levy. Pharmacologic target-mediated drug disposition. Clin. Pharmacol. Ther. 56:248–252 (1994).

    Google Scholar 

  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. 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. 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. 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. V. L. Shepherd. Intracellular pathways and mechanisms of sorting in receptor-mediated endocytosis. Trends Pharmacol. Sci. 10:458–462 (1989).

    Google Scholar 

  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. 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. 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. J. E. Rothman and F. T. Wieland. Protein sorting by transport vesicles. Science. 272:227–234 (1996).

    Google Scholar 

  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. D. Z. D'Argenio and A. Schumitzky. ADAPT II user's guide. Biomedical Simulations Resource, Los Angeles (1997).

    Google Scholar 

  13. M. Gibaldi and D. Perrier. Pharmacokinetics, Marcel Dekker, Inc., New York, 1982.

    Google Scholar 

  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. 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. 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. 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. 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. J. H. Lin. Dose-dependent pharmacokinetics: experimental observations and theoretical considerations. Biopharm. Drug Dispos. 15:1–31 (1994).

    Google Scholar 

  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. 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. 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. 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. M. Clozel. Endothelin receptor antagonists: current status and perspectives. J. Cardioû asc. Pharmacol. 35:S65–S68 (2000).

    Google Scholar 

  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. 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. 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. J. H. Noseworthy, C. Lucchinetti, M. Rodriguez, and B. G. Weinshenker. Multiple Sclerosis. NEJM 343:938–952 (2000).

    Google Scholar 

  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. 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. R. Wills. Clinical pharmacokinetics of interferons. Clin. Pharmacokinet. 19:390–399 (1990).

    Google Scholar 

  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. 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. 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. 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. 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. 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. 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. 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. 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. 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. D. E. Mager and W. J. Jusko. Pharmacodynamic modeling of time-dependent transduction systems. Clin. Pharmacol. Ther. 70:210–216 (2001).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14260

    Donald E. Mager & William J. Jusko

Authors
  1. Donald E. Mager
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William J. Jusko
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mager, D.E., Jusko, W.J. General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition. J Pharmacokinet Pharmacodyn 28, 507–532 (2001). https://doi.org/10.1023/A:1014414520282

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1014414520282

Search

Navigation