HANDLING COVARIATES IN POPULATION PHARMACOKINETICS

Population models were developed to analyze processes, described by pa rametric models, from measurements obtained in a sample of individuals . In order to analyze the sources of interindividual variability, cova riates may be incorporated in the population analysis. The exploratory analyses and the two-stage approaches which use standard non-linear r egression techniques are simple tools to select meaningful covariates. The global population approaches may be divided into two classes with in which the covariates are handled differently: the parametric and th e non-parametric methods. The power as well as the limitations of each approach regarding handling of covariates are illustrated and compare d using the same data set which concerns the pharmacokinetics of genta micin in neonates. With parametric approaches a second-stage model bet ween structural parameters and covariates has to be defined. In the no n-parametric method the joint distribution of parameters and covariate s is estimated without parametric assumptions; however, it is assumed that covariates are observed with some error and parameters involved i n functional relationships ai e not estimated. The important results c oncerning gentamicin in neonates were found by the two methods.