Intravenous Vedolizumab for IBD May Have Positive Exposure-Response Relationship

Niels Vande Casteele, PharmD, PhD

Intravenous vedolizumab was associated with a positive exposure-response relationship in patients with inflammatory bowel disease (IBD), according to new real-world findings.

A team led by Niels Vande Casteele, PharmD, PhD, University of California San Diego School of Medicine, conducted the ERELATE Study, a phase 4, multinational, retrospective, observational study, which assessed the relation between IV exposure to vedolizumab – a gut-selective humanized monoclonal antibody targeting α4β7 integrin – as well as treatment outcomes over 52 weeks.

“Although emerging real-world data further support a role for reactive TDM [therapeutic drug monitoring] during vedolizumab therapy, additional evidence is needed to support implementation in routine clinical practice and for further evaluation of vedolizumab drug concentrations, along with a range of different therapeutic outcomes,” Casteele’s team wrote.

As such, they analyzed real-world data from patients diagnosed with ulcerative colitis (n = 304) or Crohn’s disease (n = 391) across 9 centers in 6 countries. The median age of the population was 39 years old, with 47.9% being male. Median disease duration was 9 years. As many as 86.9% were previously exposed to a tumor necrosis factor (TNF) antagonist. The team observed patient outcomes at weeks 14, 26, and 52.

The primary outcome sought by the investigators was clinical remission, defined as “complete resolution of IBD-related symptoms for UC and CD according to a retrospective local physician global assessment (PGA).”

Achieving Clinical Remission

At the end of the induction period--or week 14--the investigators found that 47.3% of all patients achieved clinical remission, while 59.6%, 30.7%, and 19.0% reached endoscopic, deep (clinical plus endoscopic), and biologic remission, respectively.

Patients who demonstrated higher vedolizumab trough concentration early on in their treatment were more likely to achieve clinical remission at later time point. As such, clinical remission at weeks 14 and 52 was associated with week 6 trough concentrations of ≥31.0 and ≥32.0 μg/ml, respectively, and week 10 concentrations of ≥32.1 μg/ml and 36.5 μg/ml, respectively.

Logistic regression analysis, according to an updated Bayesian population pharmacokinetic (PK) model – which combined patients with ulcerative colitis and Crohn’s disease – showed that remission was associated with older age at baseline, induction period vedolizumab clearance, prior IBD surgery, concomitant immunosuppressant use, and albumin concentration at baseline.

Concomitant immunosuppressant use at baseline and prior IBD surgery were linked to deep remission at Week 14, and baseline vedolizumab clearance, concomitant immunosuppressant use at baseline, and prior IBD surgery were linked to deep remission at Week 52.

Expansiveness of Study Leads to New Insights

Casteel and colleagues stressed the expansiveness of the study, noting it to be the large exposure–response analysis of real-world vedolizumab data to date.

“Results from this real-world study provide valuable new insights into the association between PK parameters and short- and long-term treatment outcomes,” they wrote. “The results also strengthen observations from the GEMINI trials, including validating the application of population PK modelling with Bayesian updating to evaluate exposure–response relationships in a real-world population.”

Investigators nonetheless cautioned against interpretating causality of the exposure-response relationship, indicating that such analyses are forthcoming in the prospective interventional ENTERPRET study, a phase 4 open-label study aimed at evaluating the effect of intravenous vedolizumab dose optimization on treatment outcomes in non-responding patients with moderately to severely active ulcerative colitis.

The study "Real-world multicentre observational study including population pharmacokinetic modelling to evaluate the exposure–response relationship of vedolizumab in inflammatory bowel disease: ERELATE Study" was published in Alimentary Pharmacology & Therapeutics.