title: Variation in transplacental transfer of tyrosine kinase inhibitors in the human perfused cotyledon model.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Translational Research Laboratory, Gustave Roussy, Villejuif.
authors: C
authors: C
authors: Jovelet
authors: Department of Pharmacology and Drug Analysis, Gustave Roussy, Villejuif.
authors: A
authors: A
authors: Seck
authors: Department of Cancer Medicine, Gustave Roussy, University of Paris Sud, Villejuif.
authors: O
authors: O
authors: Mir
authors: PremUp Foundation, Paris.
authors: C
authors: C
authors: Simasotchi
authors: Department of Pharmacology and Drug Analysis, Gustave Roussy, Villejuif.
authors: S
authors: S
authors: Broutin
authors: PremUp Foundation, Paris Department of Gynaecology and Obstetrics, Teaching Hospital Cochin, Assistance Publique-Hôpitaux de Paris, DHU 'Risks in Pregnancy', University Paris Descartes, Paris.
authors: F
authors: F
authors: Goffinet
authors: Department of Medical Biology and Pathology, Gustave Roussy, Villejuif.
authors: J M
authors: JM
authors: Bidart
authors: Department of Pharmacology and Drug Analysis, Gustave Roussy, Villejuif.
authors: A
authors: A
authors: Paci
authors: PremUp Foundation, Paris UMR-S 1139, INSERM, Paris Descartes University, Paris, France sophie.gil@parisdescartes.fr.
authors: S
authors: S
authors: Gil
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000493:pharmacokinetics; D005260:Female; D005333:Fetus / Q000187:drug effects*; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008431:Maternal-Fetal Exchange; D009154:Mutation / Q000235:genetics; D010477:Perfusion; D010920:Placenta / Q000187:drug effects* / Q000502:physiology*; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068877:Imatinib Mesylate; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: lung cancer; placental transfer; pregnancy; tyrosine kinase inhibitors