Identification of the effect of multiple polymorphisms on the pharmacokinetics of Simvastatin and Simvastatin acid using a population-modeling approach

N. Tsamandouras, G. Dickinson, Y. Guo, S. Hall, A. Rostami-Hodjegan, A. Galetin, L. Aarons

    Research output: Contribution to journalArticlepeer-review

    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. © 2014 American Society for Clinical Pharmacology and Therapeutics.
    Original languageEnglish
    Pages (from-to)90-100
    Number of pages10
    JournalClinical Pharmacology and Therapeutics
    Volume96
    Issue number1
    DOIs
    Publication statusPublished - 2014

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