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

Clinical pharmacology and therapeutics (2014-03-07)
N Tsamandouras, G Dickinson, Y Guo, S Hall, A Rostami-Hodjegan, A Galetin, L Aarons
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Simvastatin, ≥97% (HPLC), solid
Supelco
Simvastatin, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Simvastatin, analytical standard
USP
Simvastatin, United States Pharmacopeia (USP) Reference Standard
Simvastatin, European Pharmacopoeia (EP) Reference Standard