Establishing Bioequivalence in Serial Sacrifice Designs
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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.
KeywordsAUC bioequivalence bootstrap Fieller’s theorem Satterthwaite’s approximation serial sacrifice design sparse sampling
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- 12.Wellek S (2003) Testing Statistical Hypothesis of Equivalence. Chapman & Hall, London, pp. 29Google Scholar
- 14.Fieller E.C. (1954). Some problems in interval estimation. J. Roy. Stat. Soc.: Ser. B 16:175–185Google Scholar
- 15.Efron B., Tibshirani R.J. (1993). An Introduction to the Bootstrap. Chapman & Hall, London, p. 160Google Scholar
- 16.R Development Core Team. R: A Language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, (2005).Google Scholar
- 17.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.Google Scholar
- 18.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.Google Scholar
- 19.Van der Vaart A.W. (1998). Asymptotic Statistics. Cambridge University Press, United Kingdom p. 26Google Scholar