A population pharmacokinetic model for simvastatin and its metabolites in children and adolescents

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Health Innovation Manchester
  • Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation
  • University of Missouri at Kansas City

Details

Original languageEnglish (US)
Pages (from-to)1227-1235
Number of pages9
JournalEuropean Journal of Clinical Pharmacology
Volume75
Issue number9
StatusPublished - Sep 1 2019
Peer-reviewedYes

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.

    Research areas

  • Children and adolescents, Metabolites, Modelling, Population pharmacokinetics, Simvastatin

Citation formats

APA

Ogungbenro, K., Wagner, J. B., Abdel-Rahman, S., Leeder, J. S., & Galetin, A. (2019). A population pharmacokinetic model for simvastatin and its metabolites in children and adolescents. European Journal of Clinical Pharmacology, 75(9), 1227-1235. https://doi.org/10.1007/s00228-019-02697-y

Harvard

Ogungbenro, K, Wagner, JB, Abdel-Rahman, S, Leeder, JS & Galetin, A 2019, 'A population pharmacokinetic model for simvastatin and its metabolites in children and adolescents', European Journal of Clinical Pharmacology, vol. 75, no. 9, pp. 1227-1235. https://doi.org/10.1007/s00228-019-02697-y