title: Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis.
abstract: OBJECTIVE
  Emerging data on selumetinib, a MEK1/2 inhibitor in clinical development, suggest a possible difference in pharmacokinetics (PK) between Japanese and Western patients. This pooled analysis sought to assess the effect of ethnicity on selumetinib exposure in healthy Western and Asian subjects, and to identify any association between genetic variants in the UGT1A1, CYP2C19 and ABCG2 genes and observed differences in selumetinib PK.
  
  
  METHODS
  A pooled analysis of data from ten Phase I studies, one in Asian subjects (encompassing Japanese, non-Japanese Asian and Indian Asian subjects) and nine in Western subjects, was conducted. Key findings were derived from the collective exposure data across doses of 25, 35, 50 and 75 mg selumetinib; primary variables were dose-normalized AUC and Cmax.
  
  
  RESULTS
  PK data from 308 subjects (10 studies) were available for the pooled analysis; genetic data from 87 subjects (3 studies) were available for the pharmacogenetic analysis. Dose-normalized AUC and Cmaxwere 35% (95% CI: 25-47%) and 39% (95% CI: 24-56%) higher in the pooled Asian group, respectively, compared with Western subjects. PK exposure parameters were similar between the Japanese, non-Japanese Asian and Indian groups. There was no evidence that the polymorphisms assessed in the genes UGT1A1, CYP2C19 and ABCG2 account for observed PK differences.
  
  
  CONCLUSIONS
  Selumetinib exposure was higher in healthy Asian subjects compared with Western subjects, and these data provide valuable insight for clinicians to consider when treating patients of Asian ethnicity with selumetinib.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.|Covance, Early Clinical Biometrics, Leeds, UK.
authors.forename: Angela W
authors.initials: AW
authors.lastname: Dymond
authors.affiliation: AstraZeneca, Personalised Healthcare & Biomarkers, Innovative Medicines and Early Development Biotech Unit, Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Elks
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.|Sandoz Pharmaceuticals, Holzkirchen, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: Early Clinical Development, Innovative Medicines and Early Development Biotech Unit, Da Vinci Building, Melbourn, Royston, Hertfordshire, SB8 6HB, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carlile
authors.affiliation: AstraZeneca Global Medicines Development, Da Vinci Building, Melbourn, Royston, Hertfordshire, SB8 6HB, UK.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Mariani
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.|Phastar Ltd, London, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Lovick
authors.affiliation: AstraZeneca, Gaithersburg, MD, 20878, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Richmond Pharmacology Ltd, St George's University of London, London, SW17 0RE, UK.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lorch
authors.affiliation: AstraZeneca, Personalised Healthcare & Biomarkers, Innovative Medicines and Early Development Biotech Unit, Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Brown
authors.affiliation: AstraZeneca Global Medicines Development, Da Vinci Building, Melbourn, Royston, Hertfordshire, SB8 6HB, UK. karen.so@astrazeneca.com.
authors.forename: Karen
authors.initials: K
authors.lastname: So
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D019540:Area Under Curve; D044466:Asian People; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D044383:Black People; D017321:Clinical Trials, Phase I as Topic; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048730:MAP Kinase Kinase Kinase 2 / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000235:genetics; D010597:Pharmacogenetics; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D044465:White People; D000099148:UGT1A1 Enzyme
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001562:Benzimidazoles; D065731:Cytochrome P-450 CYP2C19; D014453:Glucuronosyltransferase; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D000099148:UGT1A1 Enzyme; C116614:ABCG2 protein, human; C517975:AZD 6244; C045793:CYP2C19 protein, human
keywords: Asian; Pharmacogenetics; Pharmacokinetics; Selumetinib; Western