Dose optimisation for Loss of Response to Vedolizumab - Pharmacokinetics and Immune Mechanisms

Bella Ungar, Karin Malickova, Jurij Hanžel, Muhammad Abu Arisha, Stephane Paul, Catia Rocha, Zohar Ben Shatach, Chaya Mushka Abitbol, Ola Haj Natour, Limor Selinger, Miri Yavzori, Ella Fudim, Orit Picard, Irit Shoval, Rami Eliakim, Uri Kopylov, Fernando Magro, Xavier Roblin, Yehuda Chowers, David DrobneMilan Lukas, Shomron Ben Horin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1707-1719
Number of pages13
JournalJournal of Crohn's and Colitis
Volume15
Issue number10
DOIs
StatePublished - 1 Oct 2021

Keywords

  • IBD
  • Vedolizumab
  • clinical outcome
  • immunology
  • pharmacokinetics

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