Time Course of Drug Effect

  • N. H. G. Holford
  • T. M. Ludden
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 110)


It has been recognized for many years (Sokolow and Edgar 1950; Swisher et al. 1954) that drug effect may on occasion be directly associated with the time course of drug or drug metabolites in the circulation. Subsequently it was also noted that the relationship between drug concentration and response could be quite complex such that the temporal relationship might be difficult to discern on first examination, e.g., warfarin (Nagashima et al. 1969). Wagner (1975) has provided a review of early work on this topic. Sheiner et al. (1979a) illustrated the usefulness of an effect compartment for linking the time course of d-tubocurarine effect to the time course of plasma concentrations. In this way the delay in onset of effect relative to concentration could be explained. Methods for describing the kinetic behavior of drug effects were further systematized by Holford and Sheiner (1981). This chapter will discuss the motivations for characterizing the time course of drug effect, outline some methodological concerns, and present the various mathematical approaches for modeling active drug and placebo effects.


Placebo Nicotine Morphine Cocaine Warfarin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abernethy DR (1988) Problematic factors in pharmacodynamic studies. In: Kroboth PD, Smith RB, Juhl RP (eds) Pharmacokinetics and pharmacodynamics: 2. Current problems and potential solutions. Whitney, Cincinnati, p 60Google Scholar
  2. Bates DM, Watts DG (1988) Nonlinear regression analysis and its applications. Wiley, New YorkCrossRefGoogle Scholar
  3. Beal SL, Sheiner LB (1991) NONMEM users guide. University of California, San FranciscoGoogle Scholar
  4. Campbell DB (1990) The use of kinetic-dynamic interactions in the evaluation of drugs. Psychopharmacology 100: 433–450PubMedCrossRefGoogle Scholar
  5. Cheng YE, Paalzow (1990) A pharmacodynamic model to predict the time dependent adaptation of dopaminergic activity during constant concentrations of haloperidol. J Pharm Pharmacol 42: 566 - 571PubMedCrossRefGoogle Scholar
  6. Chiou WL (1991) The significance of marked “universal” dependence of drug concentration on blood sampling site in pharmacokinetics and pharmacodynamics. In: DArgenio DZ (ed) Advanced methods of pharmacokinetic and pharmacodynamic systems analysis. Plenun, New York, pp 37–54Google Scholar
  7. Colburn WA (1981) Simultaneous pharmacokinetic and pharmacodynamic modeling. J Pharmacokinet Biopharm 9: 367–388PubMedCrossRefGoogle Scholar
  8. Colburn WA, Blue JW (1992) Using pharmacokinetics and pharmacodynamics to direct pharmaceutical R&D. Appl Clin Trials 1: 42–46Google Scholar
  9. Collins JM, Grieshaber CK, Chabner BA (1990) Pharmacologically guided phase I clinical trials based upon preclinical drug development. J Natl Cancer Inst 82: 1321–1326PubMedCrossRefGoogle Scholar
  10. Dingemanse J, Danhof M, Breimer DD (1988) Pharmacokinetic-pharmacodynamic modeling of CNS drug effects: an overview. Pharmacol Ther 38: 1–52PubMedCrossRefGoogle Scholar
  11. Ebling WF, Lee EN, Stanski DR (1990) Understanding pharmacokinetics and pharmacodynamics through computer simulation: 1. The comparative clinical profiles of fentanyl and alfentanil. Anesthesiology 72: 650–658PubMedCrossRefGoogle Scholar
  12. Ekblom M, Gardmark, Hammarlund-Udenaes M (1993) Pharmacokinetics and pharmacodynamics of morphine-3-glucuronide in rats and its influence on the antinociceptive effect of morphine. Biopharm Drug Dispos (in press)Google Scholar
  13. Fisher LE, Ludwig EA, Wald JA, Sloan RR, Middleton E Jr, Jusko WJ (1992) Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM. Clin Pharmacol Ther 51: 677–688PubMedCrossRefGoogle Scholar
  14. Francheteau P, Steimer J-L, Dubray C, Lavene D (1991) Mathematical model for in vivo pharmacodynamics integrating fluctuation of the response: application to the prolactin suppressant effect of the dopaminomimetic drug DCN 203–922. J Pharmacokinet Biopharm 19: 287–309PubMedCrossRefGoogle Scholar
  15. Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New YorkGoogle Scholar
  16. Girard P, Boissel J-P (1989) Clockwise hysteresis or proteresis. J Pharmacokinet Biopharm 17: 401–402PubMedCrossRefGoogle Scholar
  17. Greenblatt DJ, Ehrenberg BL, Gunderman J, Locniskar A, Scavone JM, Harmatz JS, Shader RI (1989) Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam and placebo. Clin Pharmacol Ther 45: 356–365PubMedCrossRefGoogle Scholar
  18. Hill AV (1910) The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 40:iv–viiGoogle Scholar
  19. Holford NHG (1986) Clinical pharmacodynamics of warfarin. Clin Pharmacokinet 11: 486–504CrossRefGoogle Scholar
  20. Holford NHG (1991) Physiological alternatives to the effect compartment model. In: D’Argenio DZ (ed) Advanced methods of pharmacokinetics and pharmacodynamics systems analysis. Plenum, New York, pp 55–60Google Scholar
  21. Holford NHG (1992a) Clinical pharmacokinetics and pharmacodynamics: the quantitative basis for therapeutics. In: Melmon KL, Morelli HF, Hoffman BB, Nierenberg DW (eds) Clinical pharmacology; basic principles in therapeutics, 3rd edn. McGraw-Hill, New YorkGoogle Scholar
  22. Holford NHG (1992b) Parametric models of the time course of drug action: the population approach. In: Rowland M, Aarons L (eds) New strategies in drug development and clinical evaluation: the population approach. EUR 13775. Commission of the European Communities, Brussels, pp 193–206Google Scholar
  23. Holford NHG, Peck CC (1992) Population pharmacodynamics and drug development. In: Van Boxtel CJ, Holford NHG, Danhof M (eds) The in vivo study of drug action. Elsevier, AmsterdamGoogle Scholar
  24. Holford NHG, Peace KE (1992a) Methodologic aspects of a population pharmacodynamics model for cognitive effects in Alzheimer’s disease treated with tacrine. Proc Natl Acad Sci USA 89: 11466–11470PubMedCrossRefGoogle Scholar
  25. Holford NHG, Peace KE (1992b) Results and validation of a population pharmacodynamics model for cognitive effects in Alzheimer’s disease treated with tacrine. Proc Natl Acad Sci USA 89: 11471–11475PubMedCrossRefGoogle Scholar
  26. Holford NHG, Sheiner LB (1981) Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6: 429–453PubMedCrossRefGoogle Scholar
  27. Holford NHG, Jonkers R, Van Boxtel CJ (1989) Comparison of a physiological pharmacokinetic-pharmacodynamic model with an effect compartment model describing the hypokalaemic effect of terbutaline with and without metoprololGoogle Scholar
  28. Inturrisi CE, Colburn WQ, Kaiko RF, Houde RW, Foley KM (1987) Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 41: 392–401PubMedCrossRefGoogle Scholar
  29. Jonkers RE, Van Boxtel CJ, Koopmans RP, Oosterhuis B (1989) A nonsteady state agonist antagonist interaction model using plasma potassium concentrations to quantify the β2-selectivity of β-blockers. J Pharmacol Exp Ther 249: 297–302PubMedGoogle Scholar
  30. Kelman AW, Sumner DJ, Whiting B (1981) Systolic time interval v. heart rate regression equations using atropine: reproducibility studies. Br J Clin Pharmacol 12: 15–20PubMedGoogle Scholar
  31. Kenakin T (1987) Pharmacologic analysis of drug-receptor interaction. Raven, New YorkGoogle Scholar
  32. Kenakin T (1992) The study of drug-receptor interactions in in vivo systems. In: Van Boxtel CJ, Holford NHG, Danhof M (eds) The in vivo study of drug action. Elsevier, AmsterdamGoogle Scholar
  33. Levy G (1985) Variability in animal and human pharmacodynamic studies. In: Rowland M, Sheiner LB, Steimer J-L (eds) Variability in drug therapy. Raven, New York, p 125Google Scholar
  34. Nagashima R, O’Reilly RA, Levy G (1969) Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin Pharmacol Ther 10: 22–35PubMedGoogle Scholar
  35. Paalzow LK (1992) Measurement and modeling of analgesic drug effect. In: Van Boxtel CJ, Holford NHG, Danhof M (eds) The in vivo study of drug action. Elsevier, AmsterdamGoogle Scholar
  36. Peck CC, Nichols Al, Baker J, Lenert LL, Ezra D (1985) Clinical pharmacodynamics of theophylline. J Allergy Clin Immunol 76: 292–297PubMedCrossRefGoogle Scholar
  37. Peck CC, Barr WH, Benet LZ et al. (1992) Opportunities for integration of pharmacokinetics, pharmacodynamics and toxicokinetics in rational drug development. Clin Pharmacol Ther 51: 465–473PubMedCrossRefGoogle Scholar
  38. Perry PJ, Pfahl BM, Holstad SG (1987) The relationship between antidepressant response and tricyclic antidepressant plasma concentrations. Clin Pharmacokinet 13: 381–392PubMedCrossRefGoogle Scholar
  39. Porchet HC, Benowitz NL, Sheiner LB (1988) Pharmacodynamic model of tolerance: application to nicotine. J Pharmacol Exp Ther 244: 231–236PubMedGoogle Scholar
  40. Ratain MJ, Schilsky RL, Conley BA, Egorin MJ (1990) Pharmacodynamics in cancer therapy. J Clin Oncol 8: 1739–1753PubMedGoogle Scholar
  41. Rowland M, Tozer TN (1989) Clinical pharmacokinetics: concepts and applications, 2nd edn. Lea and Febiger, PhiladelphiaGoogle Scholar
  42. Sanaathanan LP, Peck CC (1991) The randomized concentration-controlled trial: an evaluation of its sample size efficiency. Controlled Clin Trials 12: 780–794CrossRefGoogle Scholar
  43. Scott JC, Stanski DR (1987) Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 240: 159–172PubMedGoogle Scholar
  44. Seber GAF, Wild CJ (1989) Nonlinear regression. Wiley, New York Segre G (1968) Kinetics of interaction between drugs and biological systems. II Farmaco 23: 907–918Google Scholar
  45. Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A, Layloff T, Viswanathan CT, Cook CE, McDowall RD, Pittman KA, Spector S (1992) Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Pharm Res 9: 588–592CrossRefGoogle Scholar
  46. Sheiner LB (1989) Clinical pharmacology and the choice between theory and empiricism. Clin Pharmacol Ther 46: 605–615PubMedCrossRefGoogle Scholar
  47. Sheiner LB (1991) The intellectual health of clinical drug evaluation. Clin Pharmacol Ther 50: 4–9PubMedCrossRefGoogle Scholar
  48. Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979a) Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 25: 358–371PubMedGoogle Scholar
  49. Sheiner LB, Beal SL, Rosenberg B (1979b) Forecasting individual pharmacokinetic parameters. Clin Pharmacol Ther 26: 294–305PubMedGoogle Scholar
  50. Sokolow M, Edgar AL (1950) Blood quinidine concentration as a guide in the treatment of cardiac arrhythmias. Circulation 1: 576–592Google Scholar
  51. Stanski DR (1992) Pharmacodynamic modeling of anesthetic EEG drug effects. Annu Rev Pharmacol Toxicol 32: 423–447PubMedCrossRefGoogle Scholar
  52. Stanski DR, Maitre PO (1990) Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age revisited. Anesthesiology 72: 412–422PubMedCrossRefGoogle Scholar
  53. Svec JM, Coleman RW, Mungall DR, Ludden TM (1985) Bayesian pharmacokinetics/pharmacodynamic forecasting of prothrombin response to warfarin therapy: preliminary evaluation. Ther Drug Monit 7: 174–180PubMedCrossRefGoogle Scholar
  54. Swisher WP, Wedell HG, Cheng JTO (1954) Studies of quinidine plasma levels and rate of decline following cessation of quinidine administration. Am Heart J 47: 449–452PubMedCrossRefGoogle Scholar
  55. Unadkat JD, Sheiner LB, Hennis PJ, Cronnelly R, Miller RD, Sharma M (1986) An integrated model for the interaction of muscle relaxants with their antagonists. J Appl Physiol 61: 1593–1598PubMedGoogle Scholar
  56. Van Boxtel CJ, Holford NHG, Danhof M (1992) The in vivo study of drug action. Elsevier, AmsterdamGoogle Scholar
  57. Verotta D, Kitts J, Rodriguez R, Coldwell J, Miller RD, Sheiner LB (1991) Reversal of neuromuscular blockade in humans by neostigmine and edrophonium: a mathematical model. J Pharmacokinet Biopharm 19: 713–729PubMedCrossRefGoogle Scholar
  58. Vozeh S, Bindschedler M, Ha H-R, Kaufmann G, Guentert TW, Follath F (1987) Pharmacodynamics of 3-hydroxyquinidine alone and in combination with quinidine in healthy persons. Am J Cardiol 59: 681–684PubMedCrossRefGoogle Scholar
  59. Wagner J (1975) Fundamentals of clinical pharmacokinetics. Drug Intelligence Publications, HamiltonGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • N. H. G. Holford
  • T. M. Ludden

There are no affiliations available

Personalised recommendations