Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics

Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15.


Purpose: 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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / blood
  • Angiogenesis Inhibitors / pharmacokinetics*
  • Axitinib
  • Biological Transport
  • Biotransformation
  • Clinical Trials, Phase I as Topic
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Imidazoles / blood
  • Imidazoles / pharmacokinetics*
  • Indazoles / blood
  • Indazoles / pharmacokinetics*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / metabolism
  • Polymorphism, Genetic*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*


  • Angiogenesis Inhibitors
  • Imidazoles
  • Indazoles
  • Isoenzymes
  • Organic Anion Transporters
  • Cytochrome P-450 Enzyme System
  • Axitinib
  • Receptors, Vascular Endothelial Growth Factor