Dose optimisation for Loss of Response to Vedolizumab— Pharmacokinetics and Immune Mechanisms. (10th April 2021)

• Record Type: Journal Article
• Authors: Ungar, Bella; Malickova, Karin; Hanžel, Jurij; Abu Arisha, Muhammad; Paul, Stephane; Rocha, Catia; Ben Shatach, Zohar; Abitbol, Chaya Mushka; Haj Natour, Ola; Selinger, Limor; Yavzori, Miri; Fudim, Ella; Picard, Orit; Shoval, Irit; Eliakim, Rami; Kopylov, Uri; Magro, Fernando; Roblin, Xavier; Chowers, Yehuda; Drobne, David; Lukas, Milan; Ben Horin, Shomron
• Is Part Of: Journal of Crohn's and colitis. Volume 15:Number 10(2021)
• Page Start: 1707
• Page End: 1719
• Publication Date: 2021-04-10
• Subjects: Vedolizumab -- IBD -- pharmacokinetics -- immunology -- clinical outcome; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjab067
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations. Methods: A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4β7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4β7 and effects on M1 and M2 macrophages were also explored. Results: A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward], pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [ p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32]. In the immune sub-study [ n = 43], free α4β7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [ p = 0.15], LP T cells [ p = 0.88], and on PB eosinophils [ p = 0.08]. Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4β7 receptors of two origins: non-internalised and newly generated α4β7, but re-binding was still complete at very low concentrations. Conclusions: These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab's immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.