title: Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population.
abstract: Ethnicity plays a modulating role in atorvastatin pharmacokinetics (PK), with Asian patients reported to have higher exposure compared with Caucasians. Therefore, it is difficult to safely extrapolate atorvastatin PK data and models across ethnic groups. This work aims to develop a population PK model for atorvastatin and its pharmacologically active metabolites specifically for the Japanese population. Subsequently, it aimed to identify genetic polymorphisms affecting atorvastatin PK in this population.
  
  
  
  Atorvastatin acid (ATA) and ortho-hydroxy-atorvastatin acid (o-OH-ATA) plasma concentrations, clinical/demographic characteristics and genotypes for 18 (3, 3, 1, 1, 7, 2 and 1 in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes, respectively) genetic polymorphisms were collected from 27 Japanese individuals (taking 10 mg atorvastatin once daily) and analysed using a population PK modelling approach.
  
  
  
  The population PK model developed (one-compartment for ATA linked through metabolite formation to an additional compartment describing the disposition of o-OH-ATA) accurately described the observed data and the associated population variability. Our analysis suggested that patients carrying one variant allele for the rs2622604 polymorphism (ABCG2) show a 55% (95% confidence interval: 16-131%) increase in atorvastatin oral bioavailability relative to the value in individuals without the variant allele.
  
  
  
  The current work reports the identification in the Japanese population of a BCRP polymorphism, not previously associated with the PK of any statin, that markedly increases ATA and o-OH-ATA exposure. The model developed may be of clinical importance to guide dosing recommendations tailored specifically for the Japanese.
authors: aManchester Pharmacy School, Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK bEli Lilly and Company, Indianapolis, Indiana, USA.
authors: Nikolaos
authors: N
authors: Tsamandouras
authors: Yingying
authors: Y
authors: Guo
authors: Thierry
authors: T
authors: Wendling
authors: Stephen
authors: S
authors: Hall
authors: Aleksandra
authors: A
authors: Galetin
authors: Leon
authors: L
authors: Aarons
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044466:Asian People / Q000208:ethnology* / Q000235:genetics; D000069059:Atorvastatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D017711:Nonlinear Dynamics; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide
chemical_list: C518963:2-hydroxyatorvastatin; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000924:Anticholesteremic Agents; D009363:Neoplasm Proteins; D000069059:Atorvastatin