(14) Infliximab clearance is decreased in 2nd and 3rd trimesters of pregnancy in inflammatory bowel disease
Maria Dorn-Rasmussen*, Ana-Marija Grišić[2,3]*, Bella Ungar, Jørn Brynskov, Johan F Ilvemark, Nils Bolstad, David J Warren, Mark A Ainsworth, Wilhelm Huisinga, Shomron Ben-Horin, Charlotte Kloft#, Casper Steenholdt#
1 Dept of Gastroenterology, Copenhagen University Hospital Herlev, Denmark 2 Dept of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany 3 Graduate Research Training Program PharMetrX, Germany 4 Dept of Gastroenterology, Sheba Medical Center Tel Hashomer & Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel 5 Dept of Medical Biochemistry, Oslo University Hospital, Oslo, Norway 6 Institute of Mathematics, Universität Potsdam, Germany * shared first authorship #shared senior authorship
Background: Infliximab (IFX) therapy during pregnancy in patients with inflammatory bowel disease (IBD) is challenged by the dilemma between maintaining adequate maternal disease control and at the same time minimizing fetal IFX exposure. IFX actively crosses placenta via neonatal Fc-receptors increasing efficiently in 2nd and 3rd trimesters often resulting in supra-maternal IFX levels in newborns. Although clinicians may thus refrain from administering IFX in 3rd trimester, potential implications of pregnancy on IFX pharmacokinetics are unknown.
Methods: Prospective cohort study including IFX treated pregnant IBD patients with ≥1 biobanked trough blood sample obtained during pregnancy (22 pregnancies; 19 women). Patients received steady IFX maintenance therapy at conception (5 mg/kg q8 n=14; 5 mg/kg q6 n=4; 10 mg/kg q6 n=1). Samples were obtained prior to pregnancy (n=119), in 1st trimester (n=16), 2nd trimester (n=18), 3rd trimester (n=7), or post-pregnancy (n=12). Data was analyzed by nonlinear mixed-effects modelling which enables characterization of drug pharmacokinetics over time and identification of patient characteristics that affect pharmacokinetic parameters.
Results: Maintenance phase dose-normalized IFX was significantly higher during 2nd trimester (median 15.0, IQR 9.8-20.5) as compared to pre-pregnancy (7.3, 2.0-11.6; p<0.01), 1st trimester (8.5, 1.4-11.5; p0.05). Similar trends were observed for 3rd trimester (13, 6.5-35.8; p>0.05) despite limited sample size. A one-compartment pharmacokinetic model with linear elimination described the data (V=18.2 L; CL 0.61 L/day). Maternal IFX exposure was influenced only by pregnancy and anti-IFX antibodies (Abs), and not by e.g., body weight, concomitant medications, disease type, or albumin. Of note, IFX clearance decreased significantly by 12% during 2nd-3rd trimesters as compared to pre- and post-pregnancy and 1st trimester, and with a trend of additional decrease from 2nd to 3rd trimester (15%). Anti-IFX Abs detected in 30% of samples increased IFX clearance by 69%, but pregnancy per se did not predispose to anti-IFX Abs.
Conclusion: IFX clearance decreases during 2nd and 3rd trimesters which leads to increased maternal IFX exposure. This suggests that pregnant IBD patients with therapeutic IFX levels during first part of pregnancy may maintain adequate IFX exposure despite a de-intensified IFX regimen in the last part of pregnancy.