title: A model-based approach to dose selection in early pediatric development.
abstract: The establishment of a rationale for determining dosing regimens in pediatric patients remains a challenge in drug development. In this investigation, we explored several methodologies to support bridging studies and evaluated the best descriptor of developmental changes that can be used as a covariate for dose adjustment in children. The proposed approach is illustrated for the antiviral drug abacavir. Using data from six pharmacokinetic studies in adults and one study in children, a model-based analysis was applied in order to characterize differences in parameter distributions and their implications for systemic exposure to abacavir. Simulations were subsequently performed to define the appropriate dosing regimen in children. Although body weight was identified as a covariate for clearance and volume, dosing recommendations calculated on the basis of mg/kg cannot be linearly applied across all weight ranges. Our analysis shows the consequences of empirical dose adjustment and the importance of priors from historical data to support dose selection in children.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Cella
authors.forename: F
authors.initials: F
authors.lastname: Gorter de Vries
authors.forename: D
authors.initials: D
authors.lastname: Burger
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: O
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D002648:Child; D002657:Child Development / Q000187:drug effects* / Q000502:physiology*; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D015224:Dideoxynucleosides / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010372:Pediatrics / Q000379:methods; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D055815:Young Adult; D000099227:Abacavir
chemical_list: D015224:Dideoxynucleosides; D004364:Pharmaceutical Preparations; D000099227:Abacavir