title: Effect of cigarette smoking on imatinib in patients in the soft tissue and bone sarcoma group of the EORTC.
abstract: OBJECTIVE
  Smoking is a potent inducer of cytochrome P450 (CYP) 1A2 and may affect the pharmacokinetics of CYP1A2 metabolized drugs. The effect of smoking on the pharmacokinetics of imatinib, which is metabolized by CYP3A4 and partly by CYP1A2, is unknown. We studied the effect of smoking on imatinib pharmacokinetics, safety, and efficacy.
  
  
  METHODS
  Imatinib pharmacokinetics, safety, and efficacy was analyzed in 45 patients with gastrointestinal stromal tumors (GIST) or soft-tissue sarcoma included in two European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials, including 15 smokers and 30 nonsmokers. Apparent oral clearance, distribution volume, elimination half-life, and dose-standardized area under the concentration curve (AUC) were assessed in 34 patients using nonlinear mixed-effect modeling.
  
  
  RESULTS
  Mean +/- SD pharmacokinetic variables in smokers (n = 9) versus nonsmokers (n = 25) groups were 9.6 +/- 5.5 versus 9.2 +/- 4.6 L/h (apparent oral clearance), 216.5 +/- 114.3 versus 207.0 +/- 116.9 L (distribution volume), 16.1 +/- 6.0 versus 16.5 +/- 6.0 h (elimination half-life), and 133.6 +/- 71.0 versus 142.3 +/- 84.0 ng h/mL mg area under the concentration curve; P > 0.05. Smokers experienced more grade 2/3 anemia (P = 0.010) and fatigue (P = 0.011) and those with GIST had a significantly shorter overall survival (P = 0.037) and time to progression (P = 0.052).
  
  
  CONCLUSIONS
  This retrospective study suggests that the pharmacokinetics of imatinib is not affected by smoking. However, smokers have an increased risk of anemia and fatigue. Smokers with GIST have a shorter overall survival and time to progression.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. p.h.van_rep@lumc.nl
authors.forename: Nielka
authors.initials: N
authors.lastname: van Erp
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Martine
authors.initials: M
authors.lastname: van Glabbeke
authors.forename: Allan
authors.initials: A
authors.lastname: Van Oosterom
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001549:Benzamides; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D012907:Smoking; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate