Document Type
Article
Publication Date
9-1-2019
Identifier
PMCID: PMC6697721 DOI: 10.1007/s00228-019-02697-y
Abstract
PURPOSE: Poor adherence to dietary/behaviour modifications as interventions for hypercholesterolemia in paediatric patients often necessitates the initiation of statin therapy. The aim of this study was to develop a joint population pharmacokinetic model for simvastatin and four metabolites in children and adolescents to investigate sources of variability in simvastatin acid exposure in this patient population, in addition to SLCO1B1 genotype status.
METHODS: Plasma concentrations of simvastatin and its four metabolites, demographic and polymorphism data for OATP1B1 and CYP3A5 were analysed utilising a population pharmacokinetic modelling approach from an existing single oral dose (10 mg < 17 years and 20 mg ≥ 18 years) pharmacokinetic dataset of 32 children and adolescents.
RESULTS: The population PK model included a one compartment disposition model for simvastatin with irregular oral absorption described by two parallel absorption processes each consisting of sequential zero and first-order processes. The data for each metabolite were described by a one-compartment disposition model with the formation and elimination apparent parameters estimated. The model confirmed the statistically significant effect of c.521T>C (rs4149056) on the pharmacokinetics of the active metabolite simvastatin acid in children/adolescents, consistent with adult data. In addition, age was identified as a covariate affecting elimination clearances of 6-hydroxymethyl simvastatin acid and 3, 5 dihydrodiol simvastatin metabolites.
CONCLUSION: The model developed describes the pharmacokinetics of simvastatin and its metabolites in children/adolescents capturing the effects of both c.521T>C and age on variability in exposure in this patient population. This joint simvastatin metabolite model is envisaged to facilitate optimisation of simvastatin dosing in children/adolescents.
Journal Title
European journal of clinical pharmacology
Volume
75
Issue
9
First Page
1227
Last Page
1235
MeSH Keywords
Simvastatin/pharmacokinetics; Child; Adolescent; Hypercholesterolemia; Simvastatin/analogs and derivatives
Keywords
Children and adolescents; Metabolites; Modelling; Population pharmacokinetics; Simvastatin
Recommended Citation
Ogungbenro K, Wagner JB, Abdel-Rahman S, Leeder JS, Galetin A. A population pharmacokinetic model for simvastatin and its metabolites in children and adolescents. Eur J Clin Pharmacol. 2019;75(9):1227-1235. doi:10.1007/s00228-019-02697-y
Included in
Cardiology Commons, Cardiovascular Diseases Commons, Medical Pharmacology Commons, Pediatrics Commons, Pharmaceutical Preparations Commons
Comments
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Publisher's Link: https://link.springer.com/article/10.1007/s00228-019-02697-y