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The importance of sample size, log-mean ratios, and intrasubject variability in the acceptance criteria of 108 bioequivalence studies

  • Pharmacokinetics and Disposition
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Abstract

Purpose

Fulfilling bioequivalence criteria with highly variable drugs is difficult. The aim of this study was to compare the importance of sample size, intrasubject variability, and the point estimate of test and reference formulations with regard to meeting bioequivalence (BE) criteria [maximum observed plasma concentration (Cmax) and area under the concentration-time curve (AUC)].

Methods

We compared 137 pairs of data from BE studies with a conventional number of subjects, approximately 31–32 volunteers, developed in the last 10 years.

Results

The third part of the studies failed to demonstrate BE, in part due to an unacceptable difference between the mean ratios (T/R) (18) but also due to high variability with small differences between formulations (17). Increasing the number of subjects is hard to justify, and expanding the confidence interval (CI) was insufficient for the most highly variable drugs.

Conclusions

Therefore, for low-variable drugs, the difference between formulations was the cornerstone of the fulfillment of BE criteria, but for highly variable drugs, the intrasubject coefficient of variability (ICV) was decisive. Our proposal is that for highly variable drugs that fall outside BE 90% CI limits could result in BE in the absence of formulation effect and maximal differences between formulations below 20%.

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Acknowledgements

All authors have been working in the Phase I Clinical Trial Unit of Clinical Pharmacology Department, La Paz University Hospital, and the Department of Pharmacology & Therapeutics, School of Medicine, Autonomous University of Madrid, Spain.

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Authors and Affiliations

  1. Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, Autonomous University of Madrid, Arzobispo Morcillo s/n, 28029, Madrid, Spain

    E. Ramirez, S. H. Lei, A. J. Carcas & J. Frias

  2. Clinical Pharmacology Department, School of Medicine, Autonomous University of Madrid, Arzobispo Morcillo s/n, 28029, Madrid, Spain

    P. Guerra, O. Laosa, B. Duque & B. Tabares

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  1. E. Ramirez
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  2. P. Guerra
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  3. O. Laosa
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  4. B. Duque
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  5. B. Tabares
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  6. S. H. Lei
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  7. A. J. Carcas
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  8. J. Frias
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Correspondence to E. Ramirez or J. Frias.

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Ramirez, E., Guerra, P., Laosa, O. et al. The importance of sample size, log-mean ratios, and intrasubject variability in the acceptance criteria of 108 bioequivalence studies. Eur J Clin Pharmacol 64, 783–793 (2008). https://doi.org/10.1007/s00228-008-0476-8

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  • DOI: https://doi.org/10.1007/s00228-008-0476-8

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