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Grišić AM, Dorn-Rasmussen M, Ungar B, et al. Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease. United European Gastroenterol J. 2021;9(1):91-101doi: 10.1177/2050640620964619.
Grišić, A. M., Dorn-Rasmussen, M., Ungar, B., Brynskov, J., Ilvemark, J. F. K. F., Bolstad, N., Warren, D. J., Ainsworth, M. A., Huisinga, W., Ben-Horin, S., Kloft, C., & Steenholdt, C. (2021). Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease. United European gastroenterology journal, 9(1), 91-101. https://doi.org/10.1177/2050640620964619
Grišić, Ana-Marija, et al. "Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease." United European gastroenterology journal vol. 9,1 (2021): 91-101. doi: https://doi.org/10.1177/2050640620964619
Grišić AM, Dorn-Rasmussen M, Ungar B, Brynskov J, Ilvemark JFKF, Bolstad N, Warren DJ, Ainsworth MA, Huisinga W, Ben-Horin S, Kloft C, Steenholdt C. Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease. United European Gastroenterol J. 2021 Feb;9(1):91-101. doi: 10.1177/2050640620964619. Epub 2021 Feb 11. PMID: 33079627; PMCID: PMC8259366.
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United European Gastroenterol J. 2021 Feb;9(1):91-101. doi: 10.1177/2050640620964619. Epub 2021 Feb 11.

Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease.

United European gastroenterology journal

Ana-Marija Grišić, Maria Dorn-Rasmussen, Bella Ungar, Jørn Brynskov, Johan F K F Ilvemark, Nils Bolstad, David J Warren, Mark A Ainsworth, Wilhelm Huisinga, Shomron Ben-Horin, Charlotte Kloft, Casper Steenholdt

Affiliations

  1. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
  2. Graduate Research Training Program, PharMetrX, Berlin, Germany.
  3. Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev, Denmark.
  4. Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel.
  5. Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
  6. Institute of Mathematics, Universität Potsdam, Potsdam, Germany.

PMID: 33079627 PMCID: PMC8259366 DOI: 10.1177/2050640620964619

Abstract

BACKGROUND: Infliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics.

METHODS: The study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed-effects population pharmacokinetic modeling.

RESULTS: Dose-normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10-21) compared to prepregnancy (7, 2-12; p = 0.003), the first trimester (9, 1-12; p = 0.04), or postpregnancy (6, interquartile range 3-11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7-36; p > 0.05). A one-compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti-infliximab antibodies, and not by pregnancy-imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre- and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester.

CONCLUSION: Infliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de-intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.

© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.

Keywords: IBD; anti-TNF; infliximab; pharmacokinetics; population modeling; pregnancy

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