title: Paediatric drug development: are population models predictive of pharmacokinetics across paediatric populations?
abstract: OBJECTIVE
  To assess the predictive value of a model-based approach for dose selection across paediatric populations in early clinical drug development.
  
  
  METHODS
  Abacavir was selected as a paradigm compound using data across a wide age range. Abacavir pharmacokinetics (PK) in children were analysed separately from infants and toddlers. Two independent models were obtained, and systemic exposure (AUC) was then simulated across populations based on the estimates from each model. Drug exposures in infants and toddlers were predicted using pharmacokinetic parameter distributions obtained from children, and the other way around.
  
  
  RESULTS
  The pharmacokinetic models (a two-compartment PK model for infants and toddlers and a one compartment PK model for children) accurately described the exposure in the population from which they were built. However, neither model predicted exposure in a different population: in infants, the median AUC (95%(-) CI) was estimated at 7.03 (6.72, 7.48) µg ml(-1) h, whilst it was predicted at 5.75 (4.82, 6.26) µg ml(-1) h; in children, the estimated median AUC was 6.96 (5.85, 7.91) µg ml(-1) h, whilst the predicted value was 6.45 (5.80, 7.01) µg ml(-1) h.
  
  
  CONCLUSIONS
  These findings suggest that the assumption of an identical (linear or nonlinear) correlation between pharmacokinetic parameters and demographic factors may not hold true across age groups. Whilst the use of modelling enables accurate characterization of pharmacokinetic properties, extrapolations based on such parameter estimates may have limited value due to differences in the impact of developmental growth across populations.
authors.affiliation: LACDR, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cella
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000367:Age Factors; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003627:Data Interpretation, Statistical; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D017277:Drug Approval / Q000379:methods; D004341:Drug Evaluation / Q000379:methods*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D000099227:Abacavir