Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel Aviv. Electronic address: firstname.lastname@example.org.
Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel Aviv.
Rambam Health Care Campus, Bruce & Ruth Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa.
Israel, and The First Affiliated Hospital of Sun-Yatsen University, Guangzhou, China.
Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel Aviv; Israel, and The First Affiliated Hospital of Sun-Yatsen University, Guangzhou, China. Electronic address: email@example.com.
BACKGROUND & AIMS:
There are few data available on the real-life pharmacokinetic and pharmacodynamics features of vedolizumab, a monoclonal antibody against integrin α4β7. We performed a prospective study of patients with inflammatory bowel diseases (IBD) treated with vedolizumab to determine serum drug concentrations, formation of anti-vedolizumab antibodies (AVAs), and integrin α4β7 saturation.
We performed a prospective study of 106 patients with IBD (67 with Crohn's disease and 39 with ulcerative colitis) treated with vedolizumab from September 2014 through March 2017 at 2 tertiary medical centers in Israel. Clinical data and serum samples were collected before and during induction and maintenance therapy. Clinical remission was defined as Harvey-Bradshaw index scores below 5 or as Simple Clinical Colitis Activity Index scores of 3 or less. We measured serum levels of vedolizumab, AVAs, and markers of inflammation. Peripheral blood mononuclear cells were obtained from some patients at designated trough timepoints and CD3+ CD45RO+ T cells were isolated from 36 samples. Cells were incubated with fluorescent-conjugated vedolizumab and flow cytometry was used to quantify α4β7 integrin saturation. We also performed flow cytometry analyses of CD3+ CD45RO+ lamina propria T cells isolated from intestinal mucosa of patients without IBD (non-IBD controls, n=6), patients with IBD not treated with vedolizumab (untreated IBD controls, n=8) and patients with IBD treated with vedolizumab (n=15).
Clinical remission was achieved by 48/106 patients (45%) by week 6 and 50/106 patients (48%) by week 14 of treatment. The median level of vedolizumab at week 6 was higher in patients in clinical remission (40.2 μg/mL) than in patients with active disease (29.7 μg/mL; P=.05). The median serum level of vedolizumab was significantly higher in patients with normal level of c-reactive protein (21.8 μg/mL vedolizumab) vs the level in those with a high level of c-reactive protein (11.9 μg/mL vedolizumab) during maintenance treatment (P=.0006). The other clinical outcomes measured were not associated with median serum level of vedolizumab at any time point examined. AVAs were detected in 17% of patients during induction therapy and 3% of patients during maintenance therapy, but did not correlate with clinical outcomes. Flow-cytometry analysis of peripheral blood memory T cells (n=36) showed near-complete occupancy of α4β7 integrin at weeks 2 and 14 and during maintenance phase, regardless of response status or drug levels. Most intestinal CD3+CD45RO+ memory T cells of healthy and IBD controls expressed α4β7 (72%; inter-quartile range, 56%-81%). In contrast, free α4β7 was detectable on only 5.6% of intestinal memory cells (inter-quartile range, 4.4%-11.2%) (P<.0001) from vedolizumab-treated patients, regardless of response.
In a prospective study of real-life patients with IBD, we associated vedolizumab drug levels with remission and level of a marker of inflammation. Integrin α4β7 was blocked in almost all T cells from patients treated with vedolizumab, regardless of serum level of the drug or response to treatment. These findings indicate a need to explore alternative mechanisms that prevent response to vedolizumab.