title: Population pharmacokinetics of rosuvastatin in pediatric patients with heterozygous familial hypercholesterolemia.
abstract: OBJECTIVE
  Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking Rosuvastatin OpeN label [CHARON; NCT01078675] and Study 4522IL/0086) were used to describe rosuvastatin pharmacokinetics in patients with heterozygous familial hypercholesterolemia aged ≥6 to <18 years.
  
  
  METHODS
  Rosuvastatin concentration-time data were analyzed via non-linear mixed-effects modeling (NONMEM), with clearance (CL/F) as the pre-defined key pharmacokinetic parameter of interest. In addition, descriptive comparisons between pediatric patients and adults (healthy and dyslipidemic) were performed. The dataset included 214 pediatric patients, with 2,029 rosuvastatin concentrations.
  
  
  RESULTS
  A linear two-compartment model with first-order absorption and elimination processes adequately described the combined dataset. Weight and gender were significant covariates for CL/F, with moderate between-patient variability remaining (coefficient of variation (CV) 40 %): CL/F in female children was approximately 30 % lower than in male children, and there was a twofold mean difference in CL/F across the observed weight range. Age was not a significant covariate after accounting for weight and gender differences. However, weight and gender only reduced between-patient variability from 45 (without covariates) to 40 % and are considered unlikely to be clinically relevant.
  
  
  CONCLUSIONS
  Rosuvastatin pharmacokinetics appeared generally predictable with respect to dose, and time (study duration) and the exposure (dose-normalized area under the plasma concentration-time curve at steady state (AUCss)) in children and adolescents appeared to be similar or lower than adult patients with dyslipidemia.
authors.affiliation: Wright Dose Ltd, Fifth Floor, Charter House, 2 Woodlands Road, Altrincham, Cheshire, UK. merran@wright-dose.com.
authors.forename: Merran
authors.initials: M
authors.lastname: Macpherson
authors.affiliation: AstraZeneca, Mölndal, Sweden. Bengt.Hamren@astrazeneca.com.
authors.forename: Bengt
authors.initials: B
authors.lastname: Hamrén
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.|Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marjet J A M
authors.initials: MJ
authors.lastname: Braamskamp
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.|Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: AstraZeneca, Mölndal, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Lundström
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Martin
mesh_terms: D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000068718:Rosuvastatin Calcium / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068718:Rosuvastatin Calcium
keywords: Children; Familial hypercholesterolemia; Pediatric; Population pharmacokinetics; Rosuvastatin