Pharmaceutical Research

, Volume 11, Issue 7, pp 966–974 | Cite as

Bioequivalence: Performance of Several Measures of Rate of Absorption

  • Frédéric Y. Bois
  • Thomas N. Tozer
  • Walter W. Hauck
  • Mei-Ling Chen
  • Rabindra Patnaik
  • Roger L. Williams
Article

Abstract

The highest point of the plasma concentration-time profile, Cmax , is currently used by regulatory agencies to assess the rate of drug absorption after single dose administration of oral products. It is, however, quite insensitive, and a number of new measures of rate have been proposed. Using simulations, several approaches toward measuring rate were tested. A set of model scenarios for drugs with typical mean characteristics and statistical distributions was investigated. Using different kinetic models of disposition, the time course of the concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of rate were evaluated by simulating crossover design clinical trials and then determining the probability of declaring bioequivalence as a function of differences in rates of absorption between test and reference formulations. All of the rate measures tested showed a degree of insensitivity to changes in rate and no universally superior measure was found. Indeed, the main conclusion is that the choice of a measure should be based on simulations of the particular situation in a bioequivalence trials.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    F. Y. Bois, T. N. Tozer, W. W. Hauck, M.-L. Chen, R. Patnaik, and R. L. Williams. Bioequivalence: performance of several measures of extent of absorption. Pharm. Res. (in press).Google Scholar
  2. 2.
    W. W. Hauck and S. Anderson. Types of bioequivalence and related statistical considerations. Int. J. Clin. Pharmacol. Ther. Toxicol. 30:181–187 (1992).Google Scholar
  3. 3.
    M. L. Chen. An alternative approach for assessment of rate of absorption in bioequivalence studies. Pharm. Res. 9:1380–1385 (1992).Google Scholar
  4. 4.
    L. Endrenyi, S. Fritsch, and W. Yan. Cmax/AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence. Int. J. Clin. Pharmacol. Ther. Toxicol. 29:394–399 (1991).Google Scholar
  5. 5.
    M. Rowland and T. N. Tozer. Clinical Pharmacokinetics: Concepts and Applications, Lea & Febiger, Philadelphia, 1989.Google Scholar
  6. 6.
    A. Racine-Poon and A. F. Smith. Population models. In D. A. Berry (ed.), Statistical Methodology in the Pharmaceutical Sciences, Marcel Dekker, Inc., New York, 1990, pp. 139–162.Google Scholar
  7. 7.
    D. J. Schuirmann. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokin. Biopharm. 15:657–680 (1987).Google Scholar
  8. 8.
    Food and Drug Administration—Office of Generic Drugs—Division of Bioequivalence. Guidance on statistical procedures for bioequivalence studies using a standard two-treatment crossover design. 1992.Google Scholar
  9. 9.
    Drug Information Association Working Group. International harmonization and consensus DIA meeting on bioavailability and bioequivalence requirements and standards. Drug Info. J. 25:471–482 (1991).Google Scholar
  10. 10.
    L. B. Sheiner. Bioequivalence revisited. Statistics in Medicine 11:1777–1788 (1992).Google Scholar
  11. 11.
    A. Rescigno. Bioequivalence. Pharmaceutical Research 9:925–928 (1992).Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Frédéric Y. Bois
    • 1
  • Thomas N. Tozer
    • 2
  • Walter W. Hauck
    • 3
  • Mei-Ling Chen
    • 5
  • Rabindra Patnaik
    • 5
  • Roger L. Williams
    • 5
  1. 1.Indoor Environment ProgramLawrence Berkeley LaboratoryBerkeley
  2. 2.School of PharmacyUniversity of California San FranciscoSan Francisco
  3. 3.Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan Francisco
  4. 4.Dept. of Clinical PharmacologyJefferson Medical CollegePhiladelphia
  5. 5.Department of Health and Human Services, Food and Drug Administration.Center for Drug Evaluation and Research, Office of Generic DrugsRockville

Personalised recommendations