title: Identification of the effect of multiple polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid using a population-modeling approach.
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.
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK.
authors.forename: N
authors.initials: N
authors.lastname: Tsamandouras
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: G
authors.initials: G
authors.lastname: Dickinson
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hall
authors.affiliation: 1] Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK [2] Simcyp Limited, Blades Enterprise Centre, Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Galetin
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK.
authors.forename: L
authors.initials: L
authors.lastname: Aarons
mesh_terms: D044466:Asian People; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D008954:Models, Biological; D011110:Polymorphism, Genetic; D012307:Risk Factors; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D044465:White People
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C063287:simvastatin acid; D019821:Simvastatin