Vedolizumab Trough Levels in Children With Anti‐Tumor Necrosis Factor Refractory Inflammatory Bowel Disease

Abstract

Objectives: Inflammatory bowel disease (IBD) can be successfully treated with vedolizumab. Studies in adult IBD patients have shown that differences in response to vedolizumab may be related to variability in vedolizumab trough levels, but in children with pediatric-onset IBD data regarding vedolizumab trough levels are not available. Thus far, the role of trough levels in pediatriconset IBD treatment remains unclear. We aimed to investigate predictors of vedolizumab trough levels in pediatric-onset IBD patients. Methods: Data from anti-tumor necrosis factor refractory pediatric-onset IBD patients who received vedolizumab were collected retrospectively. Vedolizumab trough levels were measured in serum samples collected before each infusion. A linear mixed model was conducted to analyze factors that influence trough levels. Results: Twenty-six pediatric-onset IBD patients (14 ulcerative colitis [UC]), 9 Crohn Disease [CD], 3 IBD-unclassified [IBD-U]) received 258 vedolizumab infusions. Mean vedolizumab trough level at week 6 was 29.9 mg/mL (SD 17.8), and 11.5 mg/mL (SD 4.9) during maintenance therapy. CD patients had significantly lower trough levels than IBD-U patients (b 15.2; 95% confidence interval [CI] À1.1 to 29.2; P ¼ 0.036). Higher fecal calprotectin (b À0.009; 95% CI À0.02 to À0.003; P ¼ 0.007) and C-reactive protein levels (b À0.4; 95% CI À0.72 to À0.04; P ¼ 0.027) were associated with lower trough levels, whereas shortening of time between infusions led to higher trough levels (b À0.77; 95% CI À0.9 to 0.64; P < 0.001). Conclusions: In this group of pediatric-onset IBD patients, trough levels were significantly lower in CD patients compared with UC/IBD-U patients. Higher levels of inflammatory markers were associated with lower vedolizumab trough levels.

Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance

“…As noted, vedolizumab PK analysis in children has been limited to sparse clinical trial data sets or data from small cohorts. These studies found elevated inflammatory markers (including CRP and FCP) and longer intervals between infusions were associated with lower cTrough 11 . Of note, CD patients had lower cTrough levels at week 2 (infusion‐2) and week 6 (infusion‐3) than UC/IBD‐U patients 11 which was also seen in this current cohort study at infusion‐4.…”

“…These studies found elevated inflammatory markers (including CRP and FCP) and longer intervals between infusions were associated with lower cTrough 11 . Of note, CD patients had lower cTrough levels at week 2 (infusion‐2) and week 6 (infusion‐3) than UC/IBD‐U patients 11 which was also seen in this current cohort study at infusion‐4. In Phase II paediatric clinical trial, UC clinical responders had higher week 14 cTroughs than non‐responders while no difference in cTrough was noted in the CD patients when stratified by the outcome 12 …”

“…Therefore, vedolizumab treatment in children is often started for patients with more severe or refractory inflammation. Prior paediatric studies found that there are unique PK needs to consider when starting vedolizumab 10,11 . Notably, a significant difference between children and adults is that vedolizumab is dosed independently of weight among most adult patients, while children weighing <30 kg will require weight‐dependent dosing (mg/kg) 12 .…”

Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab

“…However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [ 19 ]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [ 20 ]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well.…”

Advances in Therapeutic Drug Monitoring in Biologic Therapies for Pediatric Inflammatory Bowel Disease

“…A recent Dutch study highlighted the exposure–efficacy relationship of VDZ in a pediatric IBD population which had failed anti-TNF. The authors concluded that a lower TL of VDZ in Crohn's disease patients vs. UC/IBD-U was due to the transmural nature of the disease and may benefit from proactive TDM and subsequent higher dosing ( 45 ).…”