Evaluation of methods for estimating population pharmacokinetic parameters. I. Michaelismenten model: Routine clinical pharmacokinetic data
 Lewis B. Sheiner,
 Stuart L. Beal
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Individual pharmacokinetic parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual variability, and residual intraindividual variability plus measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters are estimated either by fitting all individual's data together as though there were no individual kinetic differences (the naive pooled data approach), or by fitting each individual's data separately, and then combining the individual parameter estimates (the twostage approach). A third approach, NONMEM, takes a middle course between these, and avoids shortcomings of each of them. A data set consisting of 124 steadystate phenytoin concentrationdosage pairs from 49 patients, obtained in the routine course of their therapy, was analyzed by each method. The resulting population parameter estimates differ considerably (population mean Km, for example, is estimated as 1.57, 5.36, and 4.44 μg/ml by the naive pooled data, twostage, and NONMEM approaches, respectively). Simulations of the data were analyzed to investigate these differences. The simulations indicate that the pooled data approach fails to estimate variabilities and produces imprecise estimates of mean kinetics. The twostage appproach produces good estimates of mean kinetics, but biased and imprecise estimates of interindividual variability. NONMEM produces accurate and precise estimates of all parameters, and also reasonable confidence intervals for them. This performance is exactly what is expected from theoretical considerations and provides empirical support for the use of NONMEM when estimating population pharmacokinetics from routine type patient data.
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 Title
 Evaluation of methods for estimating population pharmacokinetic parameters. I. Michaelismenten model: Routine clinical pharmacokinetic data
 Journal

Journal of Pharmacokinetics and Biopharmaceutics
Volume 8, Issue 6 , pp 553571
 Cover Date
 19801201
 DOI
 10.1007/BF01060053
 Print ISSN
 0090466X
 Online ISSN
 15738744
 Publisher
 Kluwer Academic PublishersPlenum Publishers
 Additional Links
 Topics
 Keywords

 nonlinear regression
 population pharmacokinetics
 MichaelisMenten model
 phenytoin
 statistics
 Industry Sectors
 Authors

 Lewis B. Sheiner ^{(1)}
 Stuart L. Beal ^{(1)}
 Author Affiliations

 1. Departments of Laboratory Medicine, and Division of Clinical Pharmacoiogy, Department of Medicine, University of California, 94143, San Francisco, CA