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The Integration of Pharmacodynamics and Pharmacokinetics in Rational Drug Development

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Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development

Abstract

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.

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References

  • Barbey, J. T., and R. L. Woosley (1986). Pharmacokinetic approach to amiodarone dosage selection. Clin. Prog. Electrophysiol. Pacing 4, 310–317.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Funck-Brentano, C., H. K. Kroemer, J. T. Lee, and D. M. Roden (1990). Propafenone. N. Engl. J. Med. 322, 518–525.

    Article  CAS  Google Scholar 

  • Gonzalez, F. J., and U. A. Meyer (1991). Molecular genetics of the debrisoquin-sparteine polymorphism. Clin. Pharmacol. Ther. 50, 233–237.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • 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 

  • Kalow, W. (1987). Genetic variation in the human hepatic cytochrome P450 system. Eur. J. Clin. Pharmacol. 31, 633–641.

    Article  PubMed  CAS  Google Scholar 

  • 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 determined

    Google Scholar 

  • polymorphic drug metabolism in the beta-blockade produced by propafenone. N. EngL. J. Med., 322 1164–1168.

    Google Scholar 

  • 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 

  • Mason, J. W. (1987). Amiodarone. N. Engl. J. Med. 1W, 455–466.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Woosley, R. L., A. J. J. Wood, and D. M. Roden (1988). Encainide. N. Engl. J. Med., 318 1107–1115.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. The Department of Pharmacology, Georgetown University Medical Center, Washington, D.C., 20007, USA

    Sally Usdin Yasuda, Sorell L. Schwartz, Anton Wellstein & Raymond L. Woosley

Authors
  1. Sally Usdin Yasuda
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  2. Sorell L. Schwartz
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  3. Anton Wellstein
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  4. Raymond L. Woosley
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Editor information

Editors and Affiliations

  1. Pharmacodynamics Research, American Cyanamid Company, Medical Research, Pearl River, New York, USA

    Avraham Yacobi Ph.D. (Director) (Director)

  2. Office of Research Resources, Center for Drug Evaluation and Research, Food and Drug Administration, Washington, D.C., USA

    Jerome P. Skelly Ph.D. (Deputy Director) (Deputy Director)

  3. Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland, USA

    Vinod P. Shah Ph.D. (Acting Deputy Associate Director for Science) (Acting Deputy Associate Director for Science)

  4. Department of Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, California, USA

    Leslie Z. Benet Ph.D., Pharm.D.(Hon.) (Professor and Chairman) (Professor and Chairman)

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© 1993 Springer Science+Business Media New York

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Yasuda, S.U., Schwartz, S.L., Wellstein, A., Woosley, R.L. (1993). The Integration of Pharmacodynamics and Pharmacokinetics in Rational Drug Development. In: Yacobi, A., Skelly, J.P., Shah, V.P., Benet, L.Z. (eds) Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-1520-0_24

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  • DOI: https://doi.org/10.1007/978-1-4757-1520-0_24

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4757-1522-4

  • Online ISBN: 978-1-4757-1520-0

  • eBook Packages: Springer Book Archive

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