Cited by 68Pharmacogenetics and Drug MetabolismLipoproteins and Cardiovascular HealthGenetic Associations and Epidemiology

Identification of the Effect of Multiple Polymorphisms on the Pharmacokinetics of Simvastatin and Simvastatin Acid Using a Population-Modeling Approach

Tsamandouras, N, Dickinson, G, Guo, Y, Hall, S, Rostami-Hodjegan, A, Galetin, A, Aarons, L·2014·Clinical Pharmacology & Therapeutics

Abstract

The aim of this work was to develop a joint population pharmacokinetic model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that incorporates the effects of multiple genetic polymorphisms and clinical/demographic characteristics. SV/SVA plasma concentrations, demographic/clinical data, and genotypes for 18 genetic variants were collected from 74 individuals (three clinical trials) and analyzed using a nonlinear mixed-effects modeling approach. The structural model that best described the data included a two- and a one-compartment disposition model for SV and SVA, respectively. Age, weight, Japanese ethnicity, and seven genetic polymorphisms-rs4149056 (SLCO1B1), rs776746 (CYP3A5), rs12422149 (SLCO2B1), rs2231142 (ABCG2), rs4148162 (ABCG2), rs4253728 (PPARA), and rs35599367 (CYP3A4)-were identified as significantly affecting model parameters. The developed model was used to assess combinations of these covariates, highlighting specific risk factors associated with altered SV/SVA pharmacokinetics, and consequently myopathy cases that cannot be solely attributed to the rs4149056 CC genotype.

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Crossref · 10.1038/clpt.2014.55

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Authors
Tsamandouras, N., Dickinson, G., Guo, Y., Hall, S., Rostami-Hodjegan, A., Galetin, A., & Aarons, L.
Affiliations
  • University of Manchester (GB)
  • Eli Lilly (United States) (US)
Corresponding author
Aarons, L
Venue
Clinical Pharmacology & Therapeutics
Publisher
Wiley
Published
2014-03-05
Volume
96
Issue
1
Pages
90-100
ISSN
  • 0009-9236 (ISSN-L)
  • 1532-6535
OpenAlex
W2142436506
Cited by
68
References
41
Citations by year
2026: 3 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 5 · 2015: 6 · 2014: 4
FWCI
7.27
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
simvastatin, simvastatin acid, pharmacokinetics, genetic polymorphism, population pharmacokinetic model, SLCO1B1, CYP3A5, SLCO2B1, ABCG2, PPARα, CYP3A4, myopathy, covariate effects, Japanese ethnicity
MeSH terms
Genotype, Humans, Models, Biological, Polymorphism, Genetic, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, White People, Asian People

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