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Implementation of an Effective Pharmacokinetics Research Program in Industry

  • Avraham Yacobi
  • Vijay K. Batra
  • Robert E. Desjardins
  • Robert D. Faulkner
  • Gabriela Nicolau
  • William R. Pool
  • Anita Shah
  • Alfred P. Tonelli

Abstract

Over the past decade the application of pharmacokinetic data in drug development has gradually increased. Today it is well recognized that successful drug development programs include meaningful supportive pharmacokinetic data. An effective pharmacokinetic program begins at the preclinical phase with well defined objectives to support pharmacology/toxicology programs, to determine effective/toxic blood concentration ranges and to help in expediting early phase I studies in man. The clinical pharmacokinetic program may be classified as follows: i) pharmacokinetics during safety and tolerance studies in man to determine key pharmacokinetic parameters including linearity over the utilized dose range, and related effective and toxic blood concentrations; ii) pivotal pharmacokinetic studies to determine metabolism profile and major active/inactive metabolite(s) in man, extent of first-pass metabolism, absolute and/or relative bioavailability, effect of food on absorption, dose proportionality, route and mechanism of elimination, bioequivalency of final dosage forms and to establish therapeutic dosing regimens; and iii) studies supporting labeling to determine pharmacokinetics in special populations, effect of disease states and interactions with concomitantly administered drugs. A successful pharmacokinetic program is done prospectively to support the design of safety evaluation studies, to assist in expediting the Phase I/II programs, and to facilitate the Phase III trials in patients.

Keywords

Blood Concentration Free Drug Concentration Preclinical Drug Development Toxicokinetic Parameter Drug Safety Evaluation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Barry, H., and A. Yacobi (1984). Preclinical toxicokinetics. In A. Yacobi and H. Barry, III, (Eds.), Experimental and Clinical Toxicokinetics. American Pharmaceutical Association, APS, Washington, pp. 1–7.Google Scholar
  2. Batra, V. K., and A. Yacobi (1989). An overview of toxicokinetics. In A. Yacobi, J. P. Skelly and V. K. Batra, (Eds.), Toxicokinetics and New Drug Development Pergamon Press, New York, pp. 1–20.Google Scholar
  3. Boxenbaum, H. (1984). Interspecies scaling, allometry, physiological time and ground plan of pharmacokinetics. J. Pharmacokinet. Biopharm. 10, 201–227.Google Scholar
  4. Campbell, D. B., and R. M. Ings (1988). New approaches to the use of pharmacokinetics in toxicology and drug development. Human Toxicol. 7, 469–479.CrossRefGoogle Scholar
  5. Collins, J. M., C. K. Grieshaber, B. A. Grieshaber, and B. A. Chadner (1990). Pharmacologically guided Phase I clinical trials based upon preclinical drug development. J. Natl. Cancer Inst. 82, 1321–1326.PubMedCrossRefGoogle Scholar
  6. Collins, J. M., D. S. Zaharko, R. L. Dedrick, and B. A. Chabner (1986). Potential roles for preclinical pharmacology in Phase I clinical trials. Cancer Treatment Reports 70, 73–80.Google Scholar
  7. de la Iglesia, F. A., and P. Greaves (1989). Role of toxicokinetics in drug safety evaluations. In A. Yacobi, J. P. Skelly and V. K. Batra, (Eds.) Toxicokinetics and New Drug Development. Pergamon Press, New York, pp. 21–32.Google Scholar
  8. Echizen, H., B. Vogelgesang, and M. Eichelbaum (1985a). Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism. Clin. Pharmacol. Ther. 38, 71–76.CrossRefGoogle Scholar
  9. Echizen, H., T. Brecht, S. Niedergasass, B. Vogelgesang, and M. Eichelbaum (1985b). The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans. Amer. Heart J. 109, 210–217.Google Scholar
  10. Eichelbaum, M., and A. Somogyi (1984). Inter-and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing. Eur. J. Clin. Pharmacol. 26, 47–53.Google Scholar
  11. Eichelbaum, M., G. Mikus, and B. Vogelgesang (1984). Pharmacokinetics of (+)-, (-)- and (+)-verapamil after intravenous administration. Br. J. Clin. Pharmacol. 17, 453–458.PubMedCrossRefGoogle Scholar
  12. Fabre, G., J. Combalbert, Y. Berger, and J. P. Cano (1990). Human hepatocytes as a key in-vitro model to improve preclinical drug development. Eur. J. Drug Metab. Pharmacokinet. 15, 165–171.PubMedCrossRefGoogle Scholar
  13. Gianni, L., L. Vigano, A. Surbone, D. Ballinari, P. Casali, C. Tarella, J. M. Collins, and G. Bonadonna (1990). Pharmacology and clinical toxicity of 4’-iodo-4’- deoxydoxorubicin: an example of successful application of pharmacokinetics to dose escalation in Phase I trials. J. Natl. Cancer Inst. 82, 469–477.Google Scholar
  14. Mordenti, J., and W. Chappel (1989). The use of interspecies scaling in toxicokinetics. In A. Yacobi, J.P. Skelly, and V.K. Batra (Eds.), Toxicokinetics and New Drug Development Pergamon Press, New York, pp. 42–96.Google Scholar
  15. Rahmani, R., B. Richard, G. Fabre, and J. P. Cano (1988). Extrapolation of preclinical pharmacokinetic data to therapeutic drug use. Xenobiotica 18 (Suppl.), 71–88.Google Scholar
  16. Yacobi, A., R. W. Krasula, and C. M. Lai (1984). Selective disposition studies in drug safety evaluation. In A. Yacobi and H. Barry, III, (Eds.), Experimental and Clinical Toxicok-inetics. American Pharmaceutical Association, APS, Washington, pp. 47–73.Google Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Avraham Yacobi
    • 1
  • Vijay K. Batra
    • 1
  • Robert E. Desjardins
    • 1
  • Robert D. Faulkner
    • 1
  • Gabriela Nicolau
    • 1
  • William R. Pool
    • 1
  • Anita Shah
    • 1
  • Alfred P. Tonelli
    • 1
  1. 1.Medical Research DivisionAmerican Cyanamid CompanyPearl RiverUSA

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