Abstract
The application of population pharmacokinetic analysis has received increasing attention in the last few years. The main goal of this report is to make investigators aware of the necessity of independent evaluation of the results obtained from a population analysis based on observational studies. We also describe with the help of a specific example (a new synthetic opiate Alfentanil) how such evaluation can be performed for parameter estimates obtained with the software system NONMEM. The method differs depending on the type of serum concentration data that are used for the evaluation. A general method is described, based on the regression model used in NONMEM, that can test for bias in the estimates af fixed and random effects independent of the number of observations per patient and dosing. Since the procedure for testing for statistically significant bias in the prediction of the average concentration and its variability can be relatively complex, we propose that generally available program packages performing estimation of the pharmacokinetic parameters from observational data should contain the necessary software to evaluate the reliability of the parameter estimates on a second data set.
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References
L. B. Sheiner, B. Rosenberg, and V. V. Marathe. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data.J. Pharmacokin. Biopharm. 5:445–479 (1977).
S. L. Beal and L. B. Sheiner.NONMEM Users Guide, Part I: Users Basic Guide, Technical Report of the Div. of Clinical Pharmacology, University of California, San Francisco, 1980.
T. H. Grasela, E. J. Antal, L. Ereshefsky, B. G. Wells, R. L. Evans, and R. B. Smith. An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug-drug interaction.Clin. Pharmacol. Ther. 42:433–441 (1987).
A. W. Kelman, A. H. Thomson, B. Whiting, S. M. Bryson, D. A. Streedman,et at. Estimation of gentamicin clearance and volume of distribution in neonates and young children.Br. J. Clin. Pharmacol. 18:685–692 (1984).
D. R. Mungall, T. M. Ludden, J. Marshall, D. W. Hawkins, R. T. Talbert,et al. Population pharmacokinetics of racemic warfarin in adult patients.J. Pharmacokin. Biopharm. 13:213–227 (1985).
P. O. Maitre, S. Vozeh, J. Heykants, D. A. Thomson, and D. R. Stanski. Population pharmacokinetics of alfentanil: The average dose-plasma concentration relationship and interindividual variability in patients.Anesthesiology 66:3–12 (1987).
L. B. Sheiner and L. Z. Benet. Premarketing observational studies of population pharmacokinetics of new drugs.Clin. Pharmacol. Ther. 38:481–487 (1985).
S. L. Beal. Population pharmacokinetic data and parameter estimation based on their first two statistical moments.Drug Metab. Rev. 14:173–193 (1984).
J. L. Steimer, A. Mallet, and F. Mentré. Estimating interindividual pharmacokinetic variability. In M. Rowland, L. B. Sheiner, and J. L. Steiner (eds.),Variability in Drug Therapy, Description, Estimation and Control, Raven Press, New York, 1985, pp. 65–111.
K. U. Blaser, S. Vozeh, H. Landolt, G. Kaufmann, J. Romppainen, and O. Gratzl. Intravenous phenytoin: A loading scheme for desired concentrations.Ann. Int. Med. 12;1029–1031 (1989).
S. Vozeh, T. Uematsu, G. F. Hauf, and F. Follath. Performance of Bayesian feedback to forecast lidocaine serum concentration: Evaluation of the prediction error and the prediction interval.J. Pharmacokin. Biopharm. 13:203–212 (1985).
S. Vozeh, T. Uematsu, L. Aarons, P. Maitre, H. Landolt, and O. Gratzl. Intravenous phenytoin loading in patients after neurosurgery and in status epilepticus. A population pharmacokinetic study.Clin. Pharmacokin. 14:122–128 (1988).
M. E. Ausems, C. C. Hug, D. R. Stanski, and A. G. L. Burm. Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery.Anesthesiology 65:362–373 (1986).
P. O. Maitre, M. E. Ausems, S. Vozeh, and D. R. Stanski. Evaluating the accuracy of using population pharmacokinetic data to predict plasma concentrations of alfentanil.Anesthesiology 68:59–67 (1988).
A. Mallet. A maximum likelihood estimation method for random coefficient regression models.Biometrika 73:645–655 (1986).
W. Niederberger, L. M. Gonasun, K. Kutz, R. Laplanche, E. Nüesch, H. M. Proskin, P. C. Rüegg, H. F. Schran, and J. L. Steimer. A population pharmacokinetic study during phase III clinical trials for the calcium antagonist PN 200-110 (isradipine). In J. M. Aiache and J. Hirtz (eds.),Proceedings of the IIIrd European Congress of Biopharmaceutics and Pharmacokinetics 24, Clinical Pharmacokinetics, Vol.3, University Press, Clermont-Ferrand, 1987, pp. 45–54.
W. J. Jusko, M. J. Gardner, A. Mangione, J. J. Schentag, J. R. Koup, and J. W. Vance. Factors affecting theophylline clearances: Age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates and ethanol.J. Pharm. Sci. 68:1358–1366 (1979).
S. Vozeh and C. Steiner. Estimates of the population pharmacokinetic parameters and performance of Bayesian feedback: A sensitivity analysis.J. Pharmacokin. Biopharm. 15:511–528 (1987).
R. V. Hogg and A. T. Craig (eds.).Introduction to Mathematical Statistics, 3rd ed., Collier Macmillan, New York, 1972.
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Supported by the Professor Max Cloëtta Foundation, Switzerland and the National Institute on Aging Grant ROI-04594.
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Vozeh, S., Maitre, P.O. & Stanski, D.R. Evaluation of population (NONMEM) pharmacokinetic parameter estimates. Journal of Pharmacokinetics and Biopharmaceutics 18, 161–173 (1990). https://doi.org/10.1007/BF01063558
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DOI: https://doi.org/10.1007/BF01063558