Journal of Pharmacokinetics and Biopharmaceutics

, Volume 9, Issue 5, pp 635–651

Evaluation of methods for estimating population pharmacokinetic parameters II. Biexponential model and experimental pharmacokinetic data

  • Lewis B. Sheiner
  • Stuart L. Beal
Article

Abstract

Individual pharmacokinetic parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual variability, and residual variability, including intraindividual variability and measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters have been estimated either by fitting all individuals' data together as though there were no individual kinetic differences, the naive pooled data (NPD) approach, or by fitting each individuals' data separately and then combining the individual parameter estimates, the two stage (TS) approach. A third approach, NONMEM, takes a middle course between these. This study provides further evidence of NONMEM's validity by comparing, using simulation, the three approaches on three types of data sets corresponding to three typical types of pharmacokinetic studies. The estimates of population parameters provided by the NPD method are poorer than those provided by either of the other methods. The estimates provided by the TS method are adequate for mean values and for residual variability, but not for interindividual kinetic variability. NONMEM's estimates are as good as those of the TS method for mean parameters and for residual variability, and considerably better for interindividual variability. The latter estimates are still not acceptable in an absolute sense. This is probably due, not to an intrinsic fault of the method (as it is in the case of the TS approach), but to an insufficient number of individuals being studied.

Key words

pharmacokinetic data analysis population pharmacokinetic parameters estimation statistics simulation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    L. B. Sheiner and S. Beal. Evaluation of methods for estimating population pharmacokinetic parameters. I. Michaelis-Menten model; routine clinical pharmacokinetic data.J Pharmacokinet. Biopharm. 8: 553–571 (1980).PubMedCrossRefGoogle Scholar
  2. 2.
    C. M. Metzler, G. L. Elfring, and A. J. McEwen.A Users Manual for NONLIN and Associated Programs. The Upjohn Co., Kalamazoo, Mich., 1974.Google Scholar
  3. 3.
    W. J. Dixon and F. J. Massey,Introduction to Statistical Analysis, 3rd ed., McGraw-Hill, New York, 1969, pp. 102–103.Google Scholar
  4. 4.
    S. L. Beal. Adaptive M estimation with independent non-identically distributed data. Unpublished PhD dissertation, University of California, Los Angeles, 1974.Google Scholar
  5. 5.
    S. L. Beal and L. B. Sheiner.NONMEM Users Guide, Part I. Technical Report, Division of Clinical Pharmacology, University of California, San Francisco, Calif., 1980.Google Scholar
  6. 6.
    R. D. Milleret al. The pharmacokinetics ofd-Tubocurarine in man with and without renal failure.J. Pharmacol. Exp. Ther. 202:1–7 (1977).PubMedGoogle Scholar
  7. 7.
    R. Williams. Ketoprofen bioavailability study #1, final report, Drug Studies Unit, University of California, San Francisco, Calif. (1979).Google Scholar
  8. 8.
    G. Box and M. Muller. A note on the generation of random normal deviates.Ann. Math. Stat. 29:610–611 (1958).CrossRefGoogle Scholar
  9. 9.
    P. Lewis, A. Goodman, and J. Miller. A pseudorandom number generator for the system 360.IBM Systems J. 8:135–146 (1969).CrossRefGoogle Scholar
  10. 10.
    W. J. Dixon and F. J. Massey.Introduction to Statistical Analysis, 3rd ed., McGraw-Hill, New York, 1969, p. 341.Google Scholar
  11. 11.
    W. J. Dixon and F. J. Massey.Introduction to Statistical Analysis, 3rd ed. McGraw-Hill, New York, 1969, p. 247.Google Scholar
  12. 12.
    F. Vogel and A. G. Matulsky.Human Genetics. Springer-Verlag, New York, 1979, pp. 587–590.Google Scholar

Copyright information

© Plenum Publishing Corporation 1981

Authors and Affiliations

  • Lewis B. Sheiner
    • 1
    • 2
  • Stuart L. Beal
    • 1
  1. 1.Department of Laboratory MedicineUniversity of CaliforniaSan Francisco
  2. 2.Department of Medicine, Division of Clinical PharmacologyUniversity of CaliforniaSan Francisco

Personalised recommendations