TY - JOUR
T1 - Variation in transplacental transfer of tyrosine kinase inhibitors in the human perfused cotyledon model
AU - Jovelet, C.
AU - Seck, A.
AU - Mir, O.
AU - Simasotchi, C.
AU - Broutin, S.
AU - Goffinet, F.
AU - Bidart, J. M.
AU - Paci, A.
AU - Gil, Sophie
N1 - Publisher Copyright:
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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 EGFRactivating mutation, during the second and third trimesters of pregnancy.
AB - 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 EGFRactivating mutation, during the second and third trimesters of pregnancy.
KW - Lung cancer
KW - Placental transfer
KW - Pregnancy
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=84946709736&partnerID=8YFLogxK
U2 - 10.1093/annonc/mdv172
DO - 10.1093/annonc/mdv172
M3 - Article
C2 - 25851627
AN - SCOPUS:84946709736
SN - 0923-7534
VL - 26
SP - 1500
EP - 1504
JO - Annals of Oncology
JF - Annals of Oncology
IS - 7
ER -