title: Pharmacokinetics of single-agent axitinib across multiple solid tumor types.
abstract: OBJECTIVE
  Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors, showed antitumor activity as a single agent against several solid tumor types in Phase II and III trials. This study was conducted to evaluate axitinib pharmacokinetics across a variety of solid tumors.
  
  
  METHODS
  The current study analyzed the pharmacokinetics of axitinib in 110 patients with non-small cell lung cancer (NSCLC), thyroid cancer, or melanoma from three Phase II trials plus 127 healthy volunteers, using nonlinear mixed-effects modeling. Boxplots of maximum observed plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of data from these tumor populations was compared to C max and AUC from the final population pharmacokinetic model developed for metastatic renal cell carcinoma (mRCC) to compare axitinib pharmacokinetics across different tumor types.
  
  
  RESULTS
  Axitinib disposition based on data from 237 subjects was best described using a two-compartment model with first-order absorption and lag time. Population estimates for systemic clearance, central volume of distribution, absorption rate constant, absolute bioavailability, and lag time were 20.1 L/h, 56.2 L, 1.26/h(-1), 0.663, and 0.448 h, respectively. Statistically significant covariates included gender on clearance, and body weight on central volume of distribution. However, predicted changes due to gender and body weight were found not clinically meaningful. The final analysis indicated that the pharmacokinetic model for mRCC was able to successfully describe axitinib pharmacokinetics in patients with NSCLC, thyroid cancer, and melanoma.
  
  
  CONCLUSIONS
  The pharmacokinetics of axitinib appears to be similar across a variety of tumor types.
authors.affiliation: Department of Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA, Michael.Tortorici@cslbehring.com.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tortorici
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.forename: Yazdi K
authors.initials: YK
authors.lastname: Pithavala
authors.forename: May
authors.initials: M
authors.lastname: Garrett
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.forename: Sinil
authors.initials: S
authors.lastname: Kim
authors.forename: John P
authors.initials: JP
authors.lastname: Fruehauf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D000077784:Axitinib; D001682:Biological Availability; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007191:Indazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D017711:Nonlinear Dynamics; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012737:Sex Factors; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib; D040262:Receptors, Vascular Endothelial Growth Factor