title: Influence of covariate distribution on the predictive performance of pharmacokinetic models in paediatric research.
abstract: OBJECTIVE
  The accuracy of model-based predictions often reported in paediatric research has not been thoroughly characterized. The aim of this exercise is therefore to evaluate the role of covariate distributions when a pharmacokinetic model is used for simulation purposes.
  
  
  METHODS
  Plasma concentrations of a hypothetical drug were simulated in a paediatric population using a pharmacokinetic model in which body weight was correlated with clearance and volume of distribution. Two subgroups of children were then selected from the overall population according to a typical study design, in which pre-specified body weight ranges (10-15 kg and 30-40 kg) were used as inclusion criteria. The simulated data sets were then analyzed using non-linear mixed effects modelling. Model performance was assessed by comparing the accuracy of AUC predictions obtained for each subgroup, based on the model derived from the overall population and by extrapolation of the model parameters across subgroups.
  
  
  RESULTS
  Our findings show that systemic exposure as well as pharmacokinetic parameters cannot be accurately predicted from the pharmacokinetic model obtained from a population with a different covariate range from the one explored during model building. Predictions were accurate only when a model was used for prediction in a subgroup of the initial population.
  
  
  CONCLUSIONS
  In contrast to current practice, the use of pharmacokinetic modelling in children should be limited to interpolations within the range of values observed during model building. Furthermore, the covariate point estimate must be kept in the model even when predictions refer to a subset different from the original population.
authors.affiliation: LACDR, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: Chiara
authors.initials: C
authors.lastname: Piana
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D019540:Area Under Curve; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D006801:Humans; D007223:Infant; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000097:blood; D010599:Pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations
keywords: covariates; model predictive power; paediatrics; simulations