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A New Exact Test for the Evaluation of Population Pharmacokinetic and/or Pharmacodynamic Models Using Random Projections

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ABSTRACT

Purpose

Within-subject dependency of observations has a strong impact on the evaluation of population pharmacokinetic (PK) and/or pharmacodynamic (PD) models. To our knowledge, none of the current model evaluation tools correctly address this issue. We present a new method with a global test and easy diagnostic plot which relies on the use of a random projection technique that allows the analysis of dependent data.

Methods

For each subject, the vector of standardised residuals is calculated and projected onto many random directions drawn uniformly from the unit sphere. Our test compares the empirical distribution of projections with their distribution under the model. Simulation studies assess the level of the test and compare its performance with common metrics including normalised prediction distribution errors and different types of weighted residuals. An application to real data is performed.

Results

In contrast to other evaluated methods, our test shows adequate level for all models and designs investigated, which confirms its good theoretical properties. The weakness of other methods is demonstrated and discussed.

Conclusions

This new test appears promising and could be used in combination with other tools to drive model evaluation in population PK/PD analyses.

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Abbreviations

KS:

Kolmogorov-Smirnov

VPC:

visual predictive check

GUD:

global uniform distance

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ACKNOWLEDGMENTS

We kindly thank the two anonymous reviewers for their useful comments which have improved the quality of the paper.

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Authors and Affiliations

  1. INRA, UMR 1331, Toxalim, F-31027, Toulouse, France

    Celine Marielle Laffont & Didier Concordet

  2. Université de Toulouse, INPT, ENVT, UPS, EIP, F-31076, Toulouse, France

    Celine Marielle Laffont & Didier Concordet

  3. Laboratoire de Biostatistique, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87614, 31076, Toulouse cedex 03, France

    Celine Marielle Laffont

Authors
  1. Celine Marielle Laffont
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  2. Didier Concordet
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Correspondence to Celine Marielle Laffont.

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Laffont, C.M., Concordet, D. A New Exact Test for the Evaluation of Population Pharmacokinetic and/or Pharmacodynamic Models Using Random Projections. Pharm Res 28, 1948–1962 (2011). https://doi.org/10.1007/s11095-011-0422-9

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  • DOI: https://doi.org/10.1007/s11095-011-0422-9

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