Effect of cigarette smoking on imatinib in patients in the soft tissue and bone sarcoma group of the EORTC.
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.
van Erp
Nielka
N
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. p.h.van_rep@lumc.nl
Gelderblom
Hans
H
van Glabbeke
Martine
M
Van Oosterom
Allan
A
Verweij
Jaap
J
Guchelaar
Henk-Jan
HJ
Debiec-Rychter
Maria
M
Peng
Bin
B
Blay
Jean-Yves
JY
Judson
Ian
I
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
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate