title: Population pharmacokinetic analysis of axitinib in healthy volunteers.
abstract: OBJECTIVE
  Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers.
  
  
  METHODS
  Plasma concentration-time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19).
  
  
  RESULTS
  A two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (Vc ), absorption rate constant (ka ) and absolute bioavailability (F) were 17.0 l h(-1) , 45.3 l, 0.523 h(-1) and 46.5%, respectively. With axitinib Form IV, ka and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected Vc , but the effect was within the estimated interindividual variability for Vc .
  
  
  CONCLUSIONS
  The analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. Vc was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted.
authors.affiliation: Pfizer Global Pharmacometrics, San Diego, CA, USA.
authors.forename: May
authors.initials: M
authors.lastname: Garrett
authors.forename: Bill
authors.initials: B
authors.lastname: Poland
authors.forename: Meghan
authors.initials: M
authors.lastname: Brennan
authors.forename: Brian
authors.initials: B
authors.lastname: Hee
authors.forename: Yazdi K
authors.initials: YK
authors.lastname: Pithavala
authors.forename: Michael A
authors.initials: MA
authors.lastname: Amantea
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D000077784:Axitinib; D001711:Biotransformation; D001835:Body Weight; D017321:Clinical Trials, Phase I as Topic; D065731:Cytochrome P-450 CYP2C19; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007191:Indazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D020533:Angiogenesis Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; D000077784:Axitinib; D065731:Cytochrome P-450 CYP2C19; D014453:Glucuronosyltransferase; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000099148:UGT1A1 Enzyme; C045793:CYP2C19 protein, human
keywords: CYP2C19 metabolizing status; UGT1A1*28 genotype; axitinib; population pharmacokinetics; vascular endothelial growth factor receptor inhibitor