title: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics.
abstract: OBJECTIVE
  Axitinib, an orally administered inhibitor of vascular endothelial growth factor 1, 2 and 3, is primarily metabolized by cytochrome P450 (CYP) 3A4/5 but is also a substrate for CYP1A2, CYP2C19, UDP-glucuronosyltransferase (UGT)1A1 and the drug transporters P-glycoprotein (encoded by the ABCB1 gene) and OATP1B1 (encoded by SLC01B1). The potential contribution of polymorphisms in genes encoding these enzymes and transporters to axitinib pharmacokinetic variability was assessed.
  
  
  METHODS
  A fixed effects meta-analysis was performed using data pooled from 11 healthy volunteer clinical pharmacology trials to investigate the potential association between axitinib exposure and major polymorphisms in these genes following a 5-mg dose of axitinib.
  
  
  RESULTS
  Up to 15 variant alleles were evaluated and up to 315 healthy volunteers per polymorphism were assayed. None of the polymorphisms analysed was a statistically significant predictor of axitinib pharmacokinetic variability. Amongst genotypes and inferred phenotypes, CYP2C19 genotype and the ABCB1 (G2677T/A) polymorphism were the closest to statistical significance in influencing axitinib pharmacokinetic variability after multiple-testing adjustment. However, no enzyme or transporter genotype/inferred phenotype contributed >5% to the overall pharmacokinetic variability of axitinib.
  
  
  CONCLUSIONS
  No statistically significant associations between the specific polymorphisms analysed and axitinib plasma exposure were observed, suggesting that genotype- or inferred phenotype-based adjustment of axitinib dose in individual subjects is not warranted.
authors.affiliation: Pfizer Research Center of Emphasis for DNA and Biofluids-Biobank, Groton, CT, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Brennan
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Williams
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Tortorici
authors.forename: Yazdi
authors.initials: Y
authors.lastname: Pithavala
authors.forename: Yingxue Cathy
authors.initials: YC
authors.lastname: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D000077784:Axitinib; D001692:Biological Transport; D001711:Biotransformation; D017321:Clinical Trials, Phase I as Topic; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics*; D007191:Indazoles / Q000097:blood / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D007527:Isoenzymes; D027361:Organic Anion Transporters; D003577:Cytochrome P-450 Enzyme System; D000077784:Axitinib; D040262:Receptors, Vascular Endothelial Growth Factor