Portal de Periódicos da CAPES

Vedolizumab Concentrations in the Breast Milk of Nursing Mothers With Inflammatory Bowel Disease

2017; Elsevier BV; Volume: 154; Issue: 3 Linguagem: Inglês

10.1053/j.gastro.2017.08.067

1528-0012

Mette Julsgaard, Jens Kjeldsen, Bo Martin Bibby, Birgitte Brock, Daniel C. Baumgart,

Reproductive System and Pregnancy

Vedolizumab, a monoclonal immunoglobulin (Ig)G1 antibody, has a favorable safety profile in nonpregnant and nonlactating patients.1Baumgart D.C. et al.Aliment Pharmacol Ther. 2016; 43: 1090-1102Crossref PubMed Scopus (150) Google Scholar The data on the safety of vedolizumab in reproduction is limited,2Julsgaard M. et al.Gut. 2017; 66: 1866-1867Crossref PubMed Scopus (22) Google Scholar, 3Mahadevan U. et al.Aliment Pharmacol Ther. 2017; 45: 941-950Crossref PubMed Scopus (92) Google Scholar with currently none available in lactating mothers. Before vedolizumab infusion, a breastmilk and a serum trough sample were collected from 5 mothers with inflammatory bowel disease (IBD) who were intentionally, fully breastfeeding their infants despite the lack of safety data. Thirty minutes after the infusion, another breastmilk and a serum sample were obtained for determination of vedolizumab concentration. Thereafter, breastmilk samples were collected twice daily for up to 14 days after the infusion of 300 mg vedolizumab. As a control, a healthy breastfeeding mother without IBD, supplied breastmilk samples once a day for 6 days. Vedolizumab concentrations were determined in duplicate by enzyme-linked immunosorbent assay per the manufacturer's instructions (IDKmonitor, Bensheim, Germany). Written informed consent was obtained from all women. The Review Board in Denmark (1-16-02-645-16) and Germany (EA2/086/17) approved the study. All women had received vedolizumab infusions before the infusion where breastmilk and serum samples were obtained (Figure 1, top Table). In all 5 cases where breastmilk samples were obtained right before the vedolizumab infusion a detectable concentration of 0.124 to 0.228 μg/mL was found. Vedolizumab was detectable in varying concentrations in all samples collected from 30 minutes to 14 days after the vedolizumab infusion (Figure 1, bottom Graphic). Vedolizumab concentration in the breastmilk peaked at 0.196 to 0.318 μg/mL on days 3 through 7. The peak vedolizumab breast milk concentration of 0.318 μg/mL was 1/179th of the corresponding concentration in serum equivalent to less than 1% (Figure 1, top Table). In all breastmilk samples from the unexposed control, vedolizumab was undetectable. If the highest vedolizumab milk concentration measured in any of the samples (0.318 μg/mL) is multiplied by the amount of milk ingested by the infant, approximately 150 mL per kilogram of bodyweight per day,4Bennett P.N. Drugs and human lactation. Elsevier. 1996; : 67-74Google Scholar the infant is estimated to receive 0.048 mg vedolizumab per kilogram bodyweight per day. Normal developmental milestones were recorded in all infants at the age of 3.5 to 10.0 months. All infants follow their national immunization program, and have received the inactive vaccines without complications. This is the first study to report that vedolizumab, similarly to infliximab and adalimumab, is excreted into breastmilk at low concentrations.5Nguyen G.C. Seow C.H. et al.Gastroenterology. 2016; 150: 734-757Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar Vedolizumab was detectable just before the infusion, indicating that the drug is detectable at any given time in between infusions. The peak vedolizumab milk concentration was less than 1% of the concentration in maternal serum. This is well under the recommended arbitrary cut off value of 10% for excretion of drugs into breast milk.4Bennett P.N. Drugs and human lactation. Elsevier. 1996; : 67-74Google Scholar IgG is primarily transferred to the offspring during pregnancy.6Hurley W.L. et al.Nutrients. 2011; 3: 442-474Crossref PubMed Scopus (448) Google Scholar Preliminary results from the PIANO registry indicate detectable serum concentrations of vedolizumab in mothers and infants at the time of delivery.7Mahadevan U. et al.Gastroenterology. 2016; 150 (abstract 437): S91-S92Abstract Full Text PDF Google Scholar This is in accordance with studies on maternal–fetal transport of other IgG antibodies, like infliximab and adalimumab.8Julsgaard M. et al.Gastroenterology. 2016; 151: 110-119Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Fully breastfed infants will primarily be consuming secretory IgA, but also a low content of IgG.6Hurley W.L. et al.Nutrients. 2011; 3: 442-474Crossref PubMed Scopus (448) Google Scholar Uptake and transport of IgG from serum across the mammary epithelial barrier into the alveolar lumen is thought to occur primarily through an Fc receptor–mediated process.6Hurley W.L. et al.Nutrients. 2011; 3: 442-474Crossref PubMed Scopus (448) Google Scholar Moreover, the Fc receptor has been identified on the mucosal surface of the human intestine, consistent with the hypothesis that the Fc receptor is involved in IgG recycling.6Hurley W.L. et al.Nutrients. 2011; 3: 442-474Crossref PubMed Scopus (448) Google Scholar Furthermore, a distinct IgG Fc binding site has been identified within the intestinal mucus.6Hurley W.L. et al.Nutrients. 2011; 3: 442-474Crossref PubMed Scopus (448) Google Scholar The IgG Fc binding protein is distinct from the Fc receptor. The Fc binding protein may block passage of IgG–antigen complexes to the enterocyte surface, thereby blocking their uptake and transport to the lamina propria, and perhaps allowing the complexes to be degraded in the intestinal lumen and excreted.6Hurley W.L. et al.Nutrients. 2011; 3: 442-474Crossref PubMed Scopus (448) Google Scholar In theory, the presence of Fc receptors in the gastrointestinal tract could lead to absorption of vedolizumab and theoretically result in negative effects in the gut. In the present study, we demonstrate that a fully breastfed infant is estimated to receive a maximum dose of 0.048 mg vedolizumab per kilogram of bodyweight per day. This minute quantity is furthermore anticipated to undergo proteolysis in the stomach, and through the IgG Fc binding protein in the gastrointestinal tract, it may undergo degradation and finally excretion. Additional, larger studies including investigation of specimens collected from the exposed infants are warranted to investigate the impact of vedolizumab exposure through breastmilk on the infant's immune system, especially for coping with enteric and pulmonary infections. The authors gratefully acknowledge the healthy controls and the patients with IBD involved in this study. Five mothers with IBD who were fully breastfeeding their infants while being treated with vedolizumab were asked to participate in this documentation study. From medical records we retrieved information on patient characteristics and medical treatment. Prior to vedolizumab infusion, a breast milk and a serum trough sample were collected. Thirty minutes after the infusion, another breast milk and a serum sample were obtained for determination of vedolizumab concentration. On the day of vedolizumab infusion, two additional milk samples were collected. Thereafter, breast milk samples were collected twice daily for up to 13 days after the infusion of 300 mg vedolizumab. All IBD patients filled-in a formula recording date and time of day for collection of the milk sample. One of the IBD patients supplied milk and serum samples in relation to two different infusions. Another IBD patients supplied an extra serum sample at day 7 after the vedolizumab infusion. A control, a healthy breast-feeding mother without IBD, who did not receive any kind of medical treatment supplied breast milk samples once a day for six days. Clotted blood samples were spun within an hour. Serum were frozen in aliquots at minus 80 degrees Celsius. Milk samples were initially kept at minus 20 degrees Celsius in the patients' home until the day after the final milk sample had been obtained. The milk samples were collected and transported on dry ice to the laboratory. Milk samples were stored at minus 80 degrees Celsius together with serum samples until analysis. Serum and milk vedolizumab concentrations were measured by enzyme-linked immunosorbent assay (ELISA) (IDKmonitor, Bensheim, Germany) according to the manufacturer's instructions. Samples were tested in duplicate and the average expressed as μg/ml serum. The coefficient of variation between assay wells was less than 10%. In case of very low or very high concentrations, the sample was re-tested in a different dilution. In case of a variation greater than 10% between the two results, a new analysis in duplicate was performed. The lower limit of detection was 0.01 μg/ml for vedolizumab. In control experiments, false-positive results for blank sera and milk were not seen. The presence of antibodies to vedolizumab was not assessed. Written informed consent was obtained from all participating women. The study was approved by the Danish Data Protection Agency (reference 1-10-72-269-16), by the Regional Ethical Review Board in Denmark (reference 1-16-02-669-16), and by Charité's institutional review board in Germany (EA2/086/17).