Variation in transplacental transfer of tyrosine kinase inhibitors in the human perfused cotyledon model

Ann Oncol. 2015 Jul;26(7):1500-4. doi: 10.1093/annonc/mdv172. Epub 2015 Apr 7.


Background: The use of tyrosine kinase inhibitors (TKis) during pregnancy in humans remains rare, and little data are available on their transplacental passage. Erlotinib and gefitinib are the first-line targeted therapy in case of stage IV nonsmall-cell lung cancer with an EGFR-activating mutation. There are no data available regarding the comparative use of these TKis in pregnant patients. We aimed to compare the transplacental transfer of gefitinib, imatinib and erlotinib, using the ex vivo method of human perfused cotyledon, and to determine the placental accumulation of TKis.

Materials and methods: Term placentas were perfused after delivery with gefitinib, imatinib and erlotinib at targeted maternal concentrations around the steady-state plasma trough concentration (i.e. 500, 1000 and 1500 ng/ml, respectively). Samples from fetal and maternal circulations were collected in order to monitor TKis concentrations. Main transfer parameters such as fetal transfer rate (FTR), clearance index (CI) and placental uptake were assessed.

Results: Mean FTR of gefitinib, imatinib and erlotinib were 16.8%, 10.6% and 31.4%, respectively. Mean CI of gefitinib, imatinib and erlotinib were 0.59, 0.48 and 0.93, respectively. Placental uptake in cotyledon was 0.030% %, 0.010% and 0.003% for gefitinib, imatinib and erlotinib, respectively, corresponding to a mean mass of 27.7 µg for gefitinib, 15.7 µg for imatinib and 6.8 µg for erlotinib.

Conclusion: The results suggest that TKis cross the placenta at therapeutic level. Particularly, erlotinib crosses the placenta at a higher rate than gefitinib or imatinib. All of them have a very low placental uptake. These data may suggest that gefitinib should be preferred to erlotinib for the treatment of pregnant woman with lung cancer harboring an EGFR-activating mutation, during the second and third trimesters of pregnancy.

Keywords: lung cancer; placental transfer; pregnancy; tyrosine kinase inhibitors.

Publication types

  • Comparative Study

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Erlotinib Hydrochloride / pharmacokinetics
  • Female
  • Fetus / drug effects*
  • Gefitinib
  • Humans
  • Imatinib Mesylate / pharmacokinetics
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Maternal-Fetal Exchange*
  • Mutation / genetics
  • Perfusion
  • Placenta / drug effects*
  • Placenta / physiology*
  • Pregnancy
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Quinazolines / pharmacokinetics
  • Tissue Distribution


  • Protein Kinase Inhibitors
  • Quinazolines
  • Imatinib Mesylate
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib