Vedolizumab Exposure Levels and Clinical Outcomes in Ulcerative Colitis

Determining the Potential for Dose Optimisation

Mark T. Osterman; Maria Rosario; Karen Lasch; Morris Barocas; Jayson D. Wilbur; Nathanael L. Dirks; Marc R. Gastonguay

Disclosures

Aliment Pharmacol Ther. 2019;49(4):408-418. 

In This Article

Abstract and Introduction

Abstract

Background: Prospectively designed studies assessing the exposure-response profile of vedolizumab are lacking. Observational exposure-response data for vedolizumab are limited and have not been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance.

Aims: To (a) investigate the vedolizumab exposure-response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short- and long-term clinical outcomes in adults with ulcerative colitis in GEMINI 1.

Methods: Propensity-score-based case-matching analysis was performed using data from GEMINI 1 and an earlier large population pharmacokinetic study, with vedolizumab clearance or concentration as predictors of clinical remission and response, adjusted for age, weight, anti-tumour necrosis factor alpha therapy history, serum albumin and faecal calprotectin concentrations. Potential vedolizumab concentration targets at weeks 6, 14 and steady state were proposed. Association between early vedolizumab concentrations at weeks 2, 4 and 6 and clinical remission at weeks 14 and 52 was evaluated.

Results: Among 693 patients with pharmacokinetic data at week 6, potential target vedolizumab concentrations at weeks 6, 14 and steady state were 37.1, 18.4 and 12.7 μg/mL respectively. Week 6 was identified as the earliest time at which vedolizumab concentrations were consistently associated with clinical remission at weeks 14 and 52.

Conclusions: In this comprehensively adjusted analysis, vedolizumab concentrations at week 6 were associated with short- and long-term remission. Potential induction and maintenance target concentrations were proposed for further study.

Introduction

Ulcerative colitis (UC) and Crohn's disease (CD) are chronic idiopathic inflammatory bowel diseases (IBDs) for which no medical cure presently exists. Patients with moderate-to-severe IBD typically require treatment with immunosuppressive medications, and biologic agents are gaining favour due to their efficacy and safety profiles.[1,2] Hypothesised mechanisms of lack or loss of response to monoclonal antibodies include increased serum clearance and development of immunogenicity, both of which may lead to a decrease in serum concentrations and decrease in clinical response rates.[3] Numerous studies of anti-tumour necrosis factor alpha (anti-TNFα) therapy have documented an association between low serum drug concentrations and low rates of favourable outcomes, such as clinical response, clinical remission and endoscopic mucosal healing.[4–7] As such, exposure-response evaluations with measurement of drug concentrations and anti-drug antibody concentrations have been increasingly utilised in an effort to optimise the use of these agents.[3,8–10]

Vedolizumab is a humanised monoclonal antibody that specifically binds to the α4β7 integrin and blocks lymphocyte interaction with mucosal addressin cell adhesion molecule-1 expressed on the endothelium of mesenteric lymph nodes and gastrointestinal mucosa.11As a result, vedolizumab impairs the migration of gut-homing lymphocytes into gastrointestinal mucosa and acts via a gut-selective mechanism of action.[11] The efficacy of vedolizumab for the treatment of active UC was demonstrated in the large, randomised, controlled trial GEMINI 1.[12] Among patients in GEMINI 1 treated with vedolizumab, 300 mg every 8 weeks (the US Food and Drug Administration [FDA]-approved labelled dosing), a trend towards increasing clinical response at week 52 with increasing vedolizumab concentration quartiles at week 46 was observed.[12] In addition, a post-hoc analysis of GEMINI 1 reported that rates of endoscopic mucosal healing at weeks 6 and 52 improved with increasing vedolizumab concentration quartiles at weeks 6 and 46 respectively.[13] A post-hoc analysis of data from the wider GEMINI clinical trial programme including patients with either UC or CD found that higher vedolizumab concentrations were associated with higher clinical remission rates.[14] Although several small real-world observational studies have evaluated vedolizumab concentrations and clinical outcomes,[15–18] the studies did not control for the influence of confounding factors on potential associations. Therefore, there is a need for further exploration in an established vedolizumab treatment population such as the participants in the vedolizumab GEMINI trials.

To date, exposure-response studies of biologics in IBD have had two important limitations: (a) they were not designed prospectively with the primary aim of making inferences about the drug exposure-response relationship; and (b) data were analysed on a population level rather than an individual level, without adjustment for variables that could potentially affect drug clearance and resulting drug concentrations, most notably disease activity/inflammatory burden, serum albumin concentration and body weight.[3,19] Therefore, studies demonstrating differences in drug concentrations between responders and nonresponders reveal considerable heterogeneity, not only in drug concentration cut-off values predictive of response, but also in drug concentration ranges between responders and nonresponders.[4,7,20–24]

Thus, given the limited information on the exposure-response relationship with vedolizumab and the paucity of adjusted exposure-response data for biologic agents used to treat IBD, the analyses herein aimed to characterise the relationship between vedolizumab exposure and response in UC using patient-level data from GEMINI 1 adjusted for variables known to affect drug clearance and serum concentration. Although methodologies such as quartile analyses and receiver operating characteristic analyses have historically been employed to evaluate the relationship between biologic drug exposure and response, these approaches have the major limitation of not accounting for confounding factors and correlations between endpoints. Consequently, propensity-score-based case-matching was used in the current analysis because one of its unique strengths is the ability to account for confounding factors. Potential vedolizumab concentration targets at important time points during treatment (weeks 6, 14 and steady state) were also proposed. Of note, the data from the week 6 proposed concentration target were generated in part to help design the currently ongoing vedolizumab dose-optimisation randomised controlled trial, ENTERPRET (NCT03029143). An additional aim was to identify whether early vedolizumab concentrations (at weeks 2, 4 and 6) were associated with improved short-term (at week 14) and long-term (at week 52) clinical outcomes in GEMINI 1.

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