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.