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- Title
Dose optimisation for Loss of Response to Vedolizumab— Pharmacokinetics and Immune Mechanisms.
- Authors
Ungar, Bella; Malickova, Karin; Hanžel, Jurij; Arisha, Muhammad Abu; Paul, Stephane; Rocha, Catia; Shatach, Zohar Ben; Abitbol, Chaya Mushka; Natour, Ola Haj; Selinger, Limor; Yavzori, Miri; Fudim, Ella; Picard, Orit; Shoval, Irit; Eliakim, Rami; Kopylov, Uri; Magro, Fernando; Roblin, Xavier; Chowers, Yehuda; Drobne, David
- 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.
- Publication
Journal of Crohn's & Colitis, 2021, Vol 15, Issue 10, p1707
- ISSN
1873-9946
- Publication type
Article
- DOI
10.1093/ecco-jcc/jjab067