Approaches to IVIVR Modelling and Statistical Analysis

  • Adrian Dunne
  • Tom O’Hara
  • John Devane
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 423)


The current general approach to the development of a level A in vivo-in vitro correlation (IVIVC) is open to criticism in two major respects. The statistical methodology used is not based on the statistical properties of the data being analysed and consequently parameter estimates may be biased and the analysis may be inefficient. The second criticism is that a linear model is used and this is clearly very restrictive and limits the number of instances where we might expect to find such a relationship. This chapter addresses both of these issues. New statistical methods for the current linear model are proposed and their effectiveness demonstrated by means of a simulation experiment. In addition, new non-linear models which are generalisations of the linear model are proposed together with appropriate statistical methodology for fitting them. These models are shown to have some promise by using them to describe the in vivo-in vitro relationship for a number of batches of an extended release drug product.


Fitted Curve Dosage Unit Proportional Odds Model Chlorpheniramine Maleate Operating Characteristic Curve 
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  1. 1.
    Gibaldi, M. and Perrier, D. (1982) Pharmacokinetics. Marcel Dekker, New York.Google Scholar
  2. 2.
    Dietrich, R., Brausse, R., Benedikt, G. and Steinijans, V.W. (1988) Feasibility of in-vitro/in-vivo correlation in the case of a new sustained-release theophylline pellet formulation. Arzneim. Forsch. Drug Res., 38, 1229–1237.Google Scholar
  3. 3.
    Hussein, Z. and Friedman, M. (1990) Release and absorption characteristics of novel theophylline sustained-release formulations: In vitro-in vivo correlation. Pharm Res., 7, 1167–1171.PubMedCrossRefGoogle Scholar
  4. 4.
    Mojaverian, R, Radwanski, E., Lin, C.C., Cho, P., Vadino, W.A. and Rosen, J.M. (1992) Correlation of in vitro release rate and in vivo absorption characteristics of four chlorpheniramine maleate extended-release formulations. Pharm. Res., 9, 450–456.PubMedCrossRefGoogle Scholar
  5. 5.
    Humbert, H., Cabiac, M.D. and Bosshardt, H. (1994) In vitro-in vivo correlation of a modified-release oral form of ketotifen: In vitro dissolution rate specification. J. Pharm. Sci., 83, 131–136.PubMedCrossRefGoogle Scholar
  6. 6.
    Hwang, S.S., Gorsline, J., Louie, J., Dye, D., Guinta, D. and Hamel, L. (1995) In vitro and in vivo evaluation of a once-daily controlled-release pseudoephedrine product. J. Clin. Pharmacol., 35, 259–267.PubMedGoogle Scholar
  7. 7.
    Polli, J.E., Crison, J.R. and Amidon, G.L. (1996) Novel approach to the analysis of in vitro-in vivo relationships. J. Pharm. Sci., 85, 753–759.PubMedCrossRefGoogle Scholar
  8. 8.
    Leeson, L.J. (1995) In vitro/in vivo correlations. Drug Information Journal, 29, 903–915.CrossRefGoogle Scholar
  9. 9.
    Snedecor, G.W. and Cochran, W.G. (1989) Statistical Methods. Iowa State University Press, Ames, Iowa.Google Scholar
  10. 10.
    USP (1988) In-vitro/in-vivo correlation for extended-release oral dosage forms. Pharmacopeial Forum, 14, 4160–4161.Google Scholar
  11. 11.
    Morrison, D.F. (1978) Multivariate Statistical Methods, McGraw-Hill, Singapore.Google Scholar
  12. 12.
    Crowder, M.J. and Hand, D.J. (1990) Analysis of Repeated Measures. Chapman and Hall, London.Google Scholar
  13. 13.
    Searle, S.R., Casella, G. and McCulloch, CE. (1992) Variance Components. Wiley, New York.CrossRefGoogle Scholar
  14. 14.
    Wolfinger, R. and O’Connell, M. (1993) Generalized linear mixed models: a pseudo-likelihood approach. J. Statist. Comput. Simul. 48, 233–243.CrossRefGoogle Scholar
  15. 15.
    Gillespie, W.R. (1992) PCDCON: Deconvolution for Pharmacokinetic Applications. Documentation for PCDCON computer program, University of Texas at Austin.Google Scholar

Copyright information

© Plenum Press, New York 1997

Authors and Affiliations

  • Adrian Dunne
    • 1
  • Tom O’Hara
    • 2
  • John Devane
    • 2
  1. 1.IVIVR Co-operative Working Group Department of StatisticsUniversity College DublinDublin 4Ireland
  2. 2.IVIVR Co-operative Working GroupÉlan Corporation plcMonksland, AthloneIreland

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