Higher Trough Vedolizumab Concentrations During Maintenance Therapy are Associated With Corticosteroid-Free Remission in Inflammatory Bowel Disease

Abstract

Background and Aims Vedolizumab is an anti-α4β7 biologic approved for ulcerative colitis [UC] and Crohn’s disease [CD]. We aimed to examine the association of maintenance vedolizumab concentrations with remission. Methods We performed a cross-sectional multi-centre study of inflammatory bowel disease [IBD] patients on maintenance vedolizumab. A homogeneous mobility shift assay [HMSA] was used to determine trough serum concentrations of vedolizumab and anti-drug antibodies [ATVs]. The primary outcome was corticosteroid-free clinical and biochemical remission defined as a composite of clinical remission, normalized C-reactive protein [CRP] and no corticosteroid use in 4 weeks. Secondary outcomes included corticosteroid-free endoscopic and deep remission. Vedolizumab concentrations were compared between patients in remission and with active disease. Logistic regression, adjusting for confounders, assessed the association between concentrations and remission. Results In total, 258 IBD patients were included [55% CD and 45% UC]. Patients in clinical and biochemical remission had significantly higher vedolizumab concentrations [12.7 µg/mL vs 10.1 µg/mL, p = 0.002]. Concentrations were also higher among patients in endoscopic and deep remission [14.2 µg/mL vs 8.5 µg/mL, p = 0.003 and 14.8 µg/mL vs 10.1 µg/mL, p = 0.01, respectively]. After controlling for potential confounders, IBD patients with vedolizumab concentrations >11.5 µg/mL were nearly 2.4 times more likely to be in corticosteroid-free clinical and biochemical remission. Only 1.6% of patients had ATVs. Conclusions In a large real-world cohort of vedolizumab maintenance concentrations, IBD patients with remission defined by objective measures [CRP and endoscopy] had significantly higher trough vedolizumab concentrations and immunogenicity was uncommon.

Systematic review with meta‐analysis: association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases

“…From 12 104 studies identified using the original search strategy, 5655 unique studies were identified. From these, 32 studies focusing on vedolizumab were identified for full text review, and five studies were included in quantitative synthesis (Figure ) . Additionally, data from five studies was qualitatively synthesized to inform vedolizumab concentrations associated with favourable outcomes .…”

“…Similarly, in the GEMINI‐2 trial in patients with Crohn's disease, steady state vedolizumab trough concentration in quartiles 2‐4 (≥7.6 μg/mL) was associated with numerically higher rates of clinical remission (83%‐89% vs quartile 1, 67%) . In an observational study, Ungaro and colleagues reported that vedolizumab trough concentration ≥11.3 μg/mL during maintenance therapy had the most optimal, yet modest, discriminatory performance for assessing the presence of corticosteroid‐free clinical and biochemical remission in patients with IBD (AUROC, 0.62; sensitivity/specificity, 0.57/0.63); specifically, in patients with ulcerative colitis, the cut‐off was ≥10.1 μg/mL (sensitivity/specificity, 0.89/0.43) and in patients with Crohn's disease, the cut‐off was ≥6.8 μg/mL (sensitivity/specificity 0.83/0.38) . A cut‐off of ≥10.7 μg/mL was most discriminative for the presence of corticosteroid‐free endoscopic remission.…”

“…In the GEMINI‐1 and GEMINI‐2 trial, using a drug‐sensitive assay, 3.7%‐4.1% patients had antibodies to vedolizumab at any time, and 0.4%‐1% patients had persistently positive antibodies on ≥2 consecutive samples . In observational studies, using drug‐tolerant assays, antibodies to vedolizumab were observed in 1.7%‐3.0% of patients during maintenance therapy . Using drug‐sensitive assays, antibodies to vedolizumab were observed in 0.1%‐2.4% of samples …”

“…Across studies, we observed that among remitters (clinical and/or endoscopic), vedolizumab trough concentration is significantly higher than nonremitters, in patients with ulcerative colitis, with similar trends in Crohn's disease that did not reach statistical significance. Several factors consistently associated with superior clinical outcomes (high albumin, low C‐reactive protein, low body mass index) are also associated with higher vedolizumab trough concentration . Hence, as observed with infliximab, it is likely that ulcerative colitis remitters have lower drug clearance and higher vedolizumab trough concentration than nonremitters.…”

“…Early TDM during induction may help more accurately identify patients where vedolizumab clearance is high and for whom early dose escalation may be helpful. Some studies have identified an independent association between early vedolizumab trough concentrations and future outcomes, beyond what may be predicted by conventional clinical parameters . Accounting for these findings, we have proposed an algorithmic approach when applying TDM for vedolizumab in clinical practice (Figure ) .…”