Identification of the Effect of Multiple Polymorphisms on the Pharmacokinetics of Simvastatin and Simvastatin Acid Using a Population‐Modeling Approach. Issue 1 (5th March 2014)

• Record Type: Journal Article
• Authors: Tsamandouras, N; Dickinson, G; Guo, Y; Hall, S; Rostami‐Hodjegan, A; Galetin, A; Aarons, L
• Is Part Of: Clinical pharmacology & therapeutics. Volume 96:Issue 1(2014)
• Page Start: 90
• Page End: 100
• Publication Date: 2014-03-05
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1038/clpt.2014.55
• Languages: English
• ISSNs: 0009-9236

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (<italic>SLCO1B1</italic>), rs776746 (<italic>CYP3A5</italic>), rs12422149 (<italic>SLCO2B1</italic>), rs2231142 (<italic>ABCG2</italic>), rs4148162 (<italic>ABCG2</italic>), rs4253728 (<italic>PPARA</italic>), and rs35599367 (<italic>CYP3A4</italic>)—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.</p> <p> <italic>Clinical Pharmacology & Therapeutics</italic> (2014); <bold>96</bold> 1, 90–100. doi:<ext-link ext-link-type="doi" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">10.1038/clpt.2014.55</ext-link></p> </abstract>