Journal
UNITED EUROPEAN GASTROENTEROLOGY JOURNAL
Volume 9, Issue 1, Pages 91-101Publisher
JOHN WILEY & SONS LTD
DOI: 10.1177/2050640620964619
Keywords
Infliximab; pharmacokinetics; IBD; pregnancy; population modelling; anti-TNF
Categories
Funding
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen
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Infliximab clearance decreases significantly in the second and third trimesters of pregnancy, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may be maintained as constant in a de-intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.
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 post-pregnancy (n = 12). Data were analyzed using nonlinear mixed-effects population pharmacokinetic modelling. Results Dose-normalized infliximab concentrations were significantly higher during the second trimester (median 15 mu g/mL/kg, interquartile range 10-21) compared to pre-pregnancy (7, 2-12; p = 0.003), the first trimester (9, 1-12; p = 0.04), or post-pregnancy (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 = 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 post-pregnancy 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.
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