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Biometrical evaluation of bioequivalence trials using a bootstrap individual direct curve comparison method

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Summary

Bioequivalence of two medicinal, or veterinary, products is established by comparing the mean of bioavailability measures, such as AUC and Cmax, following administration of the test (T) and reference (R) products. However, the use of these parameters has several drawbacks, e.g. they do not take into consideration the overall pharmacokinetic profile shape. Therefore, concerns have been raised regarding their appropriateness for assessment of bioequivalence. To overcome the limitations of these bioequivalence parameters, direct curve comparison metrics methods were recently proposed on an average basis. In this paper, an individual based direct curve comparison method for assessing bioequivalence is proposed. The bioequivalence of T and R in each subject is evaluated by a new curve comparison metrics δ. The metrics δ is the absolute sum of the difference between two curves. The significance of the metrics for each subject is assessed by bootstrapping. An overall bioequivalence of T and R may be considered if less than 25% of the subjects show statistically different profiles.

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References

  1. CPMP/EWP/QWP/1401/98 (2001) Note for Guidance on the Investigation of Bioavailability and Bioequivalence.

  2. CVMP/III/8090/89 (1992) Conduct of Bioequivalence Studies in Animals.

  3. Shuirmann D.J. (1987): A comparison of the two one-sided tests procedure and the power approach for assessing the bioequivalence of average bioavailability. J. Pharmacokinet. Biopharm., 15, 657–680.

    Article  Google Scholar 

  4. Zintzaras E. and Bouka P. (1999): Bioequivalence studies: blometrical concepts of alternative designs and pooled analysis. Eur. J. of Drug. Metab. and Pharmacokinet., 24, 225–232.

    Article  CAS  Google Scholar 

  5. Chen M.L., Lesko I., Williams R. (2001): Measures of Exposure versus Measures of Rate and Extent of Absorption. Clin. Pharmacokinet, 40, 565–572.

    Article  CAS  PubMed  Google Scholar 

  6. Rescigno A. (1992): Bioequivalence Pharm. Res., 9, 925–928.

    Article  CAS  PubMed  Google Scholar 

  7. Marston S.A. and Polli J.E. (1997): Evaluation of direct curve comparison metrics applied to pharmacokinetic profiles and relative bioavailability and bioequivalence. Pharm. Res. 14, 1363–1369.

    Article  CAS  PubMed  Google Scholar 

  8. Polli JE., McLean AM. (2001): Novel Direct Curve Comparison Metrics for Bioequivalence. Pharm Res., 18, 734–741.

    Article  CAS  PubMed  Google Scholar 

  9. Tozer T.N., Bois F.Y., Hauck W.W., Chen M.L., Williams R.L. (1996) Absorption rate vs exposure: Which is more useful for bioequivalence testing? Pharm. Res., 13, 453–456.

    Article  CAS  PubMed  Google Scholar 

  10. Langenbucher F. (1999): IVIVC: indices for comparing release and response profiles. Drug. Dev Ind Pharm., 25, 1223–5.

    Article  CAS  PubMed  Google Scholar 

  11. Shah VP., Tsong Y., Sathe P, Liu JP. (1998): In vitro dissolution profile comparison-statistics and analysis of the similarity factor, 12. Pharm. Res. 15, 889–896.

    Article  CAS  PubMed  Google Scholar 

  12. Chow S.C., and Liu J.P. (1992): Design and analysis of bioavailability and bioequivalence studies. New York: Marcel Dekker.

    Google Scholar 

  13. Anderson S. and Hauck W.W. (1990): Consideration of individual bioequivalence. J. Pharmacokinet. Biopharm., 18, 259–273.

    Article  CAS  PubMed  Google Scholar 

  14. Hauck W.W. and Anderson S. (1992): Types of Bioequivalence and related statistical considerations. Int. J. Clin. Pharmacol. Ther. Toxicol., 30, 181–187.

    CAS  PubMed  Google Scholar 

  15. Food and Drug Administration Center for Drug Evaluation and Research (2001) Guidance for Industry: Statistical Approaches to Establishing Bioequivalence.

  16. Chen ML., Lesko LJ. (2001): Individual Bioequivalence revisited Clin. Pharmacokinet., 40, 701–706.

    Article  CAS  PubMed  Google Scholar 

  17. Chen ML, Patnaik R, Hauck WW, Shuirmann DJ, Hyslop T, William R. (2000) An Individual Bioequivalence Criterion: regulatory considerations. Stat. Med., 19, 2821–2842.

    Article  CAS  PubMed  Google Scholar 

  18. Hauck W.W., Hyslop T, Chen ML, Patnaik R, William R. (2000): Subject-by-Formulation Interaction in Bioequivalence: Conseptual and Statistical Issues. Pharm. Research., 17, 375–380.

    Article  CAS  Google Scholar 

  19. Efron B. and Tibshirani R. (1986) An Introduction to the Bootstrap. London: Chapman and Hall.

    Google Scholar 

  20. Zintzaras E (2000) The existence of sequence effect in cross-over Bioequivalence trials. Europ. J. Drug Metab. Pharmacokinet., 25, 241–244.

    CAS  Google Scholar 

  21. Jones B. and Kenward M.G. (1995) Design and Analysis of Cross-Over Trials. London: Chapman and Hall.

    Google Scholar 

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Authors and Affiliations

  1. N.AG.RE.F., Aigialeias 19 & Chalepa, 151 25, Athens, Greece

    E. Zintzaras

  2. Hellenic Organization for Medicines, Athens, Greece

    P. Bouka

  3. Max Planck Institute, Berlin, Germany

    A. Kowald

Authors
  1. E. Zintzaras
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  2. P. Bouka
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  3. A. Kowald
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Correspondence to E. Zintzaras.

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Zintzaras, E., Bouka, P. & Kowald, A. Biometrical evaluation of bioequivalence trials using a bootstrap individual direct curve comparison method. Eur. J. Drug Metab. Pharmacokinet. 27, 11–16 (2002). https://doi.org/10.1007/BF03190400

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  • DOI: https://doi.org/10.1007/BF03190400

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