Abstract
Purpose
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.
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Acknowledgments
This study was supported by AstraZeneca. Medical writing support was provided by Melanie More of Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. Carl-Christer Johansson and Daniel Röshammar of AstraZeneca assisted with analysis of the data.
Author contributions
M. Macpherson: data analysis and interpretation and drafting the manuscript.
P.D. Martin: data analysis and interpretation.
B. Hamrén: data analysis and interpretation and drafting the manuscript.
T. Lundström: data analysis and interpretation.
J.J.P. Kastelein: data collection, data analysis, and interpretation.
M.J.A.M. Braamskamp: data collection, data analysis, and interpretation.
All authors revised the manuscript critically for important intellectual content at each stage of development, approved the final version of the manuscript for publication, and agreed to be accountable for all aspects of the work.
Conflict of interest
P.D. Martin is an employee of AstraZeneca, Macclesfield, UK. M. Macpherson is a former employee of AstraZeneca, Macclesfield, UK. B. Hamrén and T. Lundström are employees of AstraZeneca, Mölndal, Sweden. P.D. Martin, M. Macpherson, and B. Hamrén are shareholders of AstraZeneca. J.J.P. Kastelein has received grant support from AstraZeneca, Pfizer, Roche, Novartis, Merck, Merck/Schering-Plough, Isis, Genzyme, and Sanofi-Aventis; lecture fees from AstraZeneca, GlaxoSmithKline, Pfizer, Novartis, Merck/Schering-Plough, Roche, Isis, and Boehringer Ingelheim; and consulting fees from AstraZeneca, Abbott, Pfizer, Isis, Genzyme, Roche, Novartis, Merck, Merck/Schering-Plough, and Sanofi-Aventis. M.J.A.M. Braamskamp has nothing to declare.
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Macpherson, M., Hamrén, B., Braamskamp, M.J.A.M. et al. Population pharmacokinetics of rosuvastatin in pediatric patients with heterozygous familial hypercholesterolemia. Eur J Clin Pharmacol 72, 19–27 (2016). https://doi.org/10.1007/s00228-015-1946-4
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DOI: https://doi.org/10.1007/s00228-015-1946-4