Nonclinical in vivo animal studies have to be completed before starting clinical studies of the pharmacokinetic behavior of a drug in human subjects. The classic complete data design, where each animal is sampled for analysis once per time point, is usually only applicable for large animals using the traditional two-stage approach. The first stage involves estimation of pharmacokinetic parameters for each animal separately and the second stage uses the individual parameter estimates for statistical inference. In the case of rats and mice, where blood sampling is restricted, the batch design or the serial sacrifice design may be applicable. In batch designs samples are taken more than once from each animal, but not at all time points. In serial sacrifice designs only one sample is taken from each animal. In this paper, three methods are presented to construct confidence intervals for the ratio of two AUCs assessed in a serial sacrifice design, which can be used to assess bioequivalence in this parameter. The presented methods are compared in a simulation study.
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References
Bailer A.J. (1988). Testing for the equality of area under the curves when using destructive measurement techniques. J. Pharmacokinet. Biopharm. 16(3):303–309
Tang-Liu D.D.-S., Burke P.J. (1988). The effect of azone on ocular levobunolol absorption: calculating the area under the curve and its standard error using tissue sampling compartments. Pharm. Res. 5(4):238–241
Nedelman J.R., Gibiansky E., Lau D.T.W., (1995). Applying Bailer’s method for AUC confidence intervals to sparse sampling. Pharm. Res. 12(1):124–128
Satterthwaite F.E., (1946). An approximate distribution of estimates of variance components. Biometrics Bull. 2:110–114
Pai S.M., Nedelman J.R., Hajian G., Gibiansky E., Batra V.K. (1996). Performance of Bailer’s method for AUC confidence intervals from sparse non-normally distributed drug concentrations in toxicokinetic studies. Pharm. Res. 13(9):1280–1282
Nedelman J.R., Gibiansky E. (1996). The variance of a better AUC estimator for sparse, destructive sampling in toxicokinetics. J. Pharm. Sci. 85(8):884–886
Gagnon R.C., Peterson J.J. (1998). Estimation of confidence intervals for area under the curve from destructively obtained pharmacokinetic data. J. Pharmacokinet. Biopharm. 26(1):87–102
Yuan J. (1993). Estimation of variance for AUC in animal studies. J. Pharm. Sci. 82(7):761–763
Wolfsegger M.J., Jaki T. (2005). Estimation of AUC from 0 to infinity in serial sacrifice designs. J. Pharmacokinet. Pharmacodyn. 32(5–6):757–766
Heinzl H. (1996). A note on testing areas under the curve when using destructive measurement techniques. J. Pharmacokinet. Biopharm. 24(6):651–655
Bailer A.J., Ruberg S.J. (1996). Randomization tests for assessing the equality of area under curves for studies using destructive sampling. J. Appl. Toxicol. 16(5):391–395
Wellek S (2003) Testing Statistical Hypothesis of Equivalence. Chapman & Hall, London, pp. 29
Hu C., Moore K.H.P., Kim Y.H., Sale M.E., (2004). Statistical issues in a modeling approach to assessing bioequivalence or PK similarity with presence of sparsely sampled subjects. J. Pharmacokinet. Pharmacodyn. 31(4):321–339
Fieller E.C. (1954). Some problems in interval estimation. J. Roy. Stat. Soc.: Ser. B 16:175–185
Efron B., Tibshirani R.J. (1993). An Introduction to the Bootstrap. Chapman & Hall, London, p. 160
R Development Core Team. R: A Language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, (2005).
Guidance for Industry. Statistical Approaches to Establishing Bioequivelence. U.S. Department of Health and Human Services Food and Drug Administration. Center for Drug Evaluation and Research (CDER), 2001. URL: http://www.fda.gov/cder/guidance/index.htm; last visited on 2006-08-08.
Guidance for Industry. Population Pharmacokinetics. U.S. Department of Health and Human Services Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER), 1999. URL: http://www.fda.gov/cder/guidance/index.htm; last visited on 2006-08-08.
Van der Vaart A.W. (1998). Asymptotic Statistics. Cambridge University Press, United Kingdom p. 26
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Wolfsegger, M.J. Establishing Bioequivalence in Serial Sacrifice Designs. J Pharmacokinet Pharmacodyn 34, 103–113 (2007). https://doi.org/10.1007/s10928-006-9037-x
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DOI: https://doi.org/10.1007/s10928-006-9037-x