Assessment of Placental Disposition of Infliximab and Etanercept in Women With Autoimmune Diseases and in the Ex Vivo Perfused Placenta

Abstract

Tumor necrosis factor (TNF) inhibitors are increasingly applied during pregnancy without clear knowledge of the impact on placenta and fetus. We assessed placental transfer and exposure to infliximab (n = 3) and etanercept (n = 3) in women with autoimmune diseases. Furthermore, we perfused healthy term placentas for 6 hours with 100 µg/mL infliximab (n = 4) or etanercept (n = 5). In pregnant women, infliximab transferred into cord blood but also entered the placenta (cord‐to‐maternal ratio of 1.6 ± 0.4, placenta‐to‐maternal ratio of 0.3 ± 0.1, n = 3). For etanercept, a cord‐to‐maternal ratio of 0.04 and placenta‐to‐maternal ratio of 0.03 was observed in one patient only. In ex vivo placenta perfusions, the extent of placental transfer did not differ between the drugs. Final concentrations in the fetal compartment for infliximab and etanercept were 0.3 ± 0.3 and 0.2 ± 0.2 µg/mL, respectively. However, in placental tissue, infliximab levels exceeded those of etanercept (19 ± 6 vs. 1 ± 3 µg/g, P < 0.001). In conclusion, tissue exposure to infliximab is higher than that of etanercept both in vivo as well as in ex vivo perfused placentas. However, initial placental transfer, as observed ex vivo, does not differ between infliximab and etanercept when administered in equal amounts. The difference in placental tissue exposure to infliximab and etanercept may be of clinical relevance and warrants further investigation. More specifically, we suggest that future studies should look into the occurrence of placental TNF inhibition and possible consequences thereof.

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

“…FcRn also mediates transport of IgG across selective barriers such as the mucosal epithelium and the placenta (78,81,82). Transplacental transport may be particularly important to considerdue to the key developmental role of Notch signaling, Notch targeting may be harmful to the fetus.…”

Analysing cord blood levels of TNF inhibitors to validate the EULAR points to consider for TNF inhibitor use during pregnancy

“…This is in line with a previous study by Eliesen et al , which reported a low cord to maternal concentration ratio of 0.04 in a patient who used etanercept until 4 days before delivery. 7 This might be explained by the shorter half-life of etanercept (circa 3 days) compared with other TNFi (8–10 days for infliximab and 14 days for certolizumab pegol and adalimumab). Both these observations might indicate that etanercept could be used beyond GA 30–32 weeks if necessary.…”

The Effect of Pregnancy and Inflammatory Bowel Disease on the Pharmacokinetics of Drugs Related to Inflammatory Bowel Disease—A Systematic Literature Review

“…A total of 12 studies [13][14][15][16][17][18][19][20][21][22][23][24] were included, of which four studies [14,15,17,21] presented data on more than one drug. Five unique drug types were found, namely infliximab (IFX), adalimumab (ADL), vedolizumab (VDZ), ustekinumab (UST) and golimumab (GLM).…”

“…In conclusion, 12 studies were found that presented drug concentrations for IFX, ADL, VDZ, UST and GLM. Most studies [16,19,20,[22][23][24] only presented a concentration at delivery. The studies that presented data during the whole pregnancy showed an increase in concentration for IFX, a relative stable concentration for ADL and a decreasing concentration for VDZ.…”