The Integration of Pharmacodynamics and Pharmacokinetics in Rational Drug Development

  • Sally Usdin Yasuda
  • Sorell L. Schwartz
  • Anton Wellstein
  • Raymond L. Woosley


Pharmacokinetic and pharmacodynamic analyses have been found to be valuable components of new drug development programs. This chapter will describe developments in pharmacokinetic and pharmacodynamic studies that have taken place in recent years. An understanding of the relationship between pharmacokinetics and pharmacodynamics and the integration of each type of study will allow even greater contributions to drug development and pharmacological research.


Receptor Occupancy PBPK Model Extensive Metabolizers Effect Compartment Radioreceptor Assay 
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  1. Barbey, J. T., and R. L. Woosley (1986). Pharmacokinetic approach to amiodarone dosage selection. Clin. Prog. Electrophysiol. Pacing 4, 310–317.Google Scholar
  2. Barbey, J. T., K. A. Thompson, D. S. Echt, R. L. Woosley, and D. M. Roden (1988). Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites 0-desmethyl encainide and 3- methoxy-O-desmethyl encainide in man. Circulation 77, 380–391.Google Scholar
  3. Benowitz, N. L. (1974). Clinical applications of the pharmacokinetics of lidocaine. In K. L. Melmon (Ed.) Cardiovascular Drug Therapy (Cardiovascular Clinics). Vol. 6. F. A. Davis, Philadelphia.Google Scholar
  4. Carey, E. L., H. J. Duff, D. M. Roden, R. K. Primm, G. R. Wilkinson, T. Wang, J. A. Oates, and R. L. Woosley (1984). Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals. J. Clin. Invest. 73, 539–547.PubMedCrossRefGoogle Scholar
  5. Connolly, S. J., R. E. Kates, C. S. Lebsack, D. C. Harrison, and R. A. Winkle (1983). Clinical pharmacology of propafenone. Circulation 68, 589–596.Google Scholar
  6. Funck-Brentano, C., H. K. Kroemer, J. T. Lee, and D. M. Roden (1990). Propafenone. N. Engl. J. Med. 322, 518–525.CrossRefGoogle Scholar
  7. Gonzalez, F. J., and U. A. Meyer (1991). Molecular genetics of the debrisoquin-sparteine polymorphism. Clin. Pharmacol. Ther. 50, 233–237.PubMedCrossRefGoogle Scholar
  8. Hou, Z. Y., N. J. Balter, R. L. Woosley, and S. L. Schwartz (1990). A Physiologically-Based Pharmacokinetic (PB-PK) Model for Desethylamiodarone. Circulation 82 (Suppl III), 196 (Abstract).Google Scholar
  9. Hou, Z. Y., S. J. Huang, S. A. Chen, C. W. Chiou, S. L. Lin, M. Lin, M. S. Chang, S. L. Schwartz, R.. L. Woosely, and C. Y. Chen (1991). Application of a simulated myocardial concentration-based amiodarone regimen in atrial fibrillation/flutter. Circulation 84 (Suppl II), II - 714.Google Scholar
  10. Jusko, W. J. (1986). 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., Spokane, Washington, pp. 9–54.Google Scholar
  11. Kalow, W. (1987). Genetic variation in the human hepatic cytochrome P450 system. Eur. J. Clin. Pharmacol. 31, 633–641.PubMedCrossRefGoogle Scholar
  12. Lee, J. T., H. K. Kroemer, D. J. Silberstein, C. Funck-Brentano, M. D. Lineberry, A. J. J. Wood, D. M. Roden, and R. L. Woosley (1990). The role of genetically determinedGoogle Scholar
  13. polymorphic drug metabolism in the beta-blockade produced by propafenone. N. EngL. J. Med., 322 1164–1168.Google Scholar
  14. Lee, J. T., M.D. Lineberry, C. Funck-Brentano, P. L. Chaffin, D. M. Roden, and R. L. Woosley (1988). Propafenone-induced ß-blockade in extensive and poor metabolizer subjects. Circulation 78 (Suppl II), 1I - 499. (Abstract)Google Scholar
  15. Mason, J. W. (1987). Amiodarone. N. Engl. J. Med. 1W, 455–466.Google Scholar
  16. McAllister, C. B., H. T. Wolfenden, W. S. Aslanian, R. L. Woosley, and G. R. Wilkinson (1986). Oxidative metabolism of encainide: Polymorphism, pharmacokinetics and clinical considerations. Xenobiotica 16, 483–490.Google Scholar
  17. McLeod, A. A., G. L. Stiles, and D. G. Shand (1984). Demonstration of beta adrenoceptor blockade by propafenone hydrochloride: clinical pharmacologic, radioligand binding, and adenylate cyclase activation studies..1. Pharmacol. Exp. Ther., 228 461–466.Google Scholar
  18. Pitschner, H. F., and A. Wellstein (1988). Dose response curves of pirenzipine in man in relation to Ml-and M2-cholinoceptor occupancy. Naunyn Schmiedebergs Arch. Pharmacol., 338 207–210.Google Scholar
  19. Pitschner, H. F., B. Schulte, M. Schlepper, D. Palm, and A. Wellstein (1989a). AF-DX 116 discriminates heart from gland M2-cholinoceptors in man. Life Sci. 45, 493–498.Google Scholar
  20. Pitschner, H. F., M. Schlepper, B. Schulte, C. Volz, D. Palm, and A. Wellstein (1989b). Selective antagonists reveal different functions of M cholinoceptor subtypes in humans. Trends Pharmacol. Sci. (Suppl), 92–96.Google Scholar
  21. Roden, D. M., J. T. Lee, R. L. Woosley, and D. S. Echt (1989). Antiarrhythmic efficacy, clinical electrophysiology, and pharmacokinetics of 3-methoxy-O-desmethyl encainide (MODE) in patients with recurrent sustained ventricular tachycardia or fibrillation. Circulation 80, 1247–1258.Google Scholar
  22. Salerno, D. M., G. Granrud, P. Sharkey, R. Asinger, and M. Hodges (1984). Controlled trial of propafenone for treatment of frequent and repetitive ventricular premature complexes. Am. J. Cardiol. 53, 77–83.PubMedCrossRefGoogle Scholar
  23. Siddoway, L. A., C. B. McAllister, G. R. Wilkinson, D. M. Roden, and R. L. Woosley (1983). Amiodarone dosing: a proposal based on its pharmacokinetics. Am. Heart J., 106 951–956.PubMedCrossRefGoogle Scholar
  24. Siddoway, L.A., K. A. Thompson, C. B. McAllister, T. Wang, G. R. Wilkinson, D. M. Roden, and R. L. Woosley (1987). Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75, 785–791.Google Scholar
  25. Stargel, W. W., D. G. Shand, P. A. Routledge, A. Barchowsky, and G. S. Wagner (1981). Clinical comparison of rapid infusion and multiple injection methods for lidocaine loading. Am. Heart J. 102, 872–876.PubMedCrossRefGoogle Scholar
  26. Wellstein, A., D. Palm, G. Weimer, M. Schafer-Korting, and E. Mutschler (1984). Simple and reliable radioreceptor assay for beta-adrenoceptor antagonists and active metabolites in native human plasma. Eur. J. Clin. Pharmacol. 27, 545–553.PubMedCrossRefGoogle Scholar
  27. Wellstein, A., D. Palm, G. G. Belz, and H. F. Pitschner (1985a). Receptor binding characteristics and pharmacokinetic properties as a tool for the prediction of clinical effects of ß-blockers. Arzneimittelforschung 35, 2–6.Google Scholar
  28. Wellstein, A., D. Palm, H. F. Pitschner, and G. G. Belz (1985b). Receptor binding of propranolol is the missing link between plasma concentration kinetics and effect-time course in man. Eur. J. Clin. Pharmacol. 29, 131–147.Google Scholar
  29. Wellstein, A., D. Palm, G. G. Belz, R. Butzer, R. Polsak, and B. Pett (1987). Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy. Eur. Heart J. 8(Suppl M), 3–8.Google Scholar
  30. Wellstein, A., G. G. Belz, and D. Palm (1988). Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1 selective bisoprolol in humans. Evaluation with Schild-Plots. J. Pharmacol. Exp. Ther., 246 328–337.Google Scholar
  31. Woosley, R. L., D. M. Roden, G. H. Dai, T. Wang, D. C. Altenbern, J. Oates, and G. R. Wilkinson (1986). Co-inheritance of the polymorphic metabolism of encainide and debrisoquin. Clin. Pharmacol. Ther. 39, 282–287.PubMedCrossRefGoogle Scholar
  32. Woosley, R. L., A. J. J. Wood, and D. M. Roden (1988). Encainide. N. Engl. J. Med., 318 1107–1115.Google Scholar
  33. Wyman, M. G., R. L. Slaughter, D. A. Farolino, S. Gore, D. S. Cannom, B. N. Goldreyer, and D. Lalka (1983). Multiple bolus technique for lidocaine administration in acute ischemic heart disease. II. Treatment of refractory ventricular arrhythmias and the pharmacokinetic significance of severe left ventricular failure. J. Am. Coll. Cardiol. 2., 764–769.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Sally Usdin Yasuda
    • 1
  • Sorell L. Schwartz
    • 1
  • Anton Wellstein
    • 1
  • Raymond L. Woosley
    • 1
  1. 1.The Department of PharmacologyGeorgetown University Medical CenterUSA

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