科研之友
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摘要
BACKGROUND & AIMS: There are few data available on the real-life pharmacokinetic and pharmacodynamics features of vedolizumab, a monoclonal antibody against integrin alpha 4 beta 7. We performed a prospective study of patients with inflammatory bowel diseases (IBDs) treated with vedolizumab to determine serum drug concentrations, formation of antivedolizumab antibodies (AVAs), and integrin alpha 4 beta 7 saturation. METHODS: 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 time points and CD3+ CD45RO+ T cells were isolated from 36 samples. Cells were incubated with fluorescent-conjugated vedolizumab and flow cytometry was used to quantify alpha 4 beta 7 integrin saturation. We also performed flow cytometry analyses of CD3D CD45ROD 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). RESULTS: Clinical remission was achieved by 48 of 106 patients (45%) by week 6 and 50 of 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 mu g/mL) than in patients with active disease (29.7 mu g/mL; P = 05). The median serum level of vedolizumab was significantly higher in patients with a normal level of C-reactive protein (21.8 mu g/mL vedolizumab) vs the level in those with a high level of C-reactive protein (11.9 mu g/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 alpha 4 beta 7 integrin at weeks 2 and 14 and during the maintenance phase, regardless of response status or drug levels. Most intestinal CD3+CD45RO+memory T cells of healthy and IBD controls expressed alpha 4 beta 7 (72%; interquartile range, 56%-81%). In contrast, free alpha 4 beta 7 was detectable on only 5.6% of intestinal memory cells (interquartile range, 4.4%-11.2%) (P < .0001) from vedolizumab-treated patients, regardless of response. CONCLUSIONS: In a prospective study of real-life patients with IBD, we associated vedolizumab drug levels with remission and inflammatory marker level. Integrin alpha 4 beta 7 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.
- 出版日期2018-5
- 单位中山大学
