Handling covariates in population pharmacokinetics.

Population models were developed to analyze processes, described by parametric models, from measurements obtained in a sample of individuals. In order to analyze the sources of interindividual variability, covariates may be incorporated in the population analysis. The exploratory analyses and the two-stage approaches which use standard non-linear regression techniques are simple tools to select meaningful covariates. The global population approaches may be divided into two classes within which the covariates are handled differently: the parametric and the non-parametric methods. The power as well as the limitations of each approach regarding handling of covariates are illustrated and compared using the same data set which concerns the pharmacokinetics of gentamicin in neonates. With parametric approaches a second-stage model between structural parameters and covariates has to be defined. In the non-parametric method the joint distribution of parameters and covariates is estimated without parametric assumptions; however, it is assumed that covariates are observed with some error and parameters involved in functional relationships are not estimated. The important results concerning gentamicin in neonates were found by the two methods.

[1]  L. Sheiner,et al.  Modelling of individual pharmacokinetics for computer-aided drug dosage. , 1972, Computers and biomedical research, an international journal.

[2]  A W Kelman,et al.  Population pharmacokinetics of gentamicin in neonates. , 1988, Developmental pharmacology and therapeutics.

[3]  G. Pons,et al.  Gentamicin Monitoring in Neonates , 1988, Therapeutic drug monitoring.

[4]  A H Thomson,et al.  Bayesian Parameter Estimation and Population Pharmacokinetics , 1992, Clinical pharmacokinetics.

[5]  J. Armijo,et al.  Time Course of Trough Serum Gentamicin Concentrations in Preterm and Term Neonates , 1992, Clinical pharmacokinetics.

[6]  D. Bates,et al.  Nonlinear mixed effects models for repeated measures data. , 1990, Biometrics.

[7]  S. E. Hills,et al.  Illustration of Bayesian Inference in Normal Data Models Using Gibbs Sampling , 1990 .

[8]  K. Rodvold,et al.  An Updated Comparison of Drug Dosing Methods , 1991, Clinical pharmacokinetics.

[9]  C. Faura,et al.  Monitoring Serum Levels of Gentamicin to Develop a New Regimen for Gentamicin Dosage in Newborns , 1991, Therapeutic drug monitoring.

[10]  J. Jais,et al.  Exploratory analysis of population pharmacokinetic data from clinical trials with application to isradipine , 1991, Clinical pharmacology and therapeutics.

[11]  R W Jelliffe,et al.  Gentamicin population pharmacokinetic models for low birth weight infants using a new nonparametric method , 1991, Clinical pharmacology and therapeutics.

[12]  J. M. Lanao,et al.  Population Pharmacokinetics of Gentamicin in Premature Infants , 1992, Therapeutic drug monitoring.

[13]  A. Mallet.  A maximum likelihood estimation method for random coefficient regression models , 1986 .

[14]  C. Faura,et al.  Changes in gentamicin serum levels and pharmacokinetic parameters in the newborn in the course of treatment with aminoglycoside. , 1991, Therapeutic drug monitoring.