title: Lack of effect of smoking status on axitinib pharmacokinetics in patients with non-small-cell lung cancer.
abstract: OBJECTIVE
  Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers.
  
  
  METHODS
  Data were pooled from six clinical studies-serial pharmacokinetics from two healthy volunteer studies (n = 58) and sparse pharmacokinetics from four NSCLC studies (n = 152)-for a nonlinear mixed effects modeling (NONMEM v7.2) analysis. Demographics, smoking status, liver and renal function status, and Eastern Cooperative Oncology Group performance status were tested as covariates.
  
  
  RESULTS
  There were 83 (40%) active smokers and 56 (27%) ex-smokers in the pooled dataset. Axitinib pharmacokinetics was adequately described with a linear, two-compartment model with a lagged first-order absorption. Final parameter estimates (inter-individual variability) were 16.1 L/h (59.1%) and 45.3 L (54.4%) for systemic clearance (CL) and central volume of distribution (Vc), respectively. Smoking status was found not to alter CL or Vc. Asian ethnicity and body weight were significant covariates for Vc, but were not considered clinically relevant since individual values of Vc for Asians were within the range of non-Asians.
  
  
  CONCLUSIONS
  Based on this analysis, smoking status does not affect area under plasma concentration-time curve, and thus no dose adjustment is required for smokers.
authors: Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA.
authors: May
authors: M
authors: Garrett
authors: Projections Research Inc, Phoenixville, PA, USA.
authors: Timothy
authors: T
authors: Taylor
authors: Projections Research Inc, Phoenixville, PA, USA.
authors: Diane R
authors: DR
authors: Mould
authors: Clinical Pharmacometrics, Pfizer Inc, San Diego, CA, USA.
authors: Michael A
authors: MA
authors: Amantea
authors: Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA.
authors: Ying
authors: Y
authors: Chen
authors: Clinical Development, Pfizer Oncology, Milan, Italy.
authors: Antonella
authors: A
authors: Ingrosso
authors: Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA. yazdi.pithavala@pfizer.com.
authors: Yazdi K
authors: YK
authors: Pithavala
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077784:Axitinib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D007191:Indazoles / Q000493:pharmacokinetics*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D012907:Smoking / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib
keywords: Axitinib; CYP1A2; Non-small-cell lung cancer; Population pharmacokinetics; Smoking status; Vascular endothelial growth factor receptor