TY - JOUR
T1 - Dose optimisation for Loss of Response to Vedolizumab - Pharmacokinetics and Immune Mechanisms
AU - Ungar, Bella
AU - Malickova, Karin
AU - Hanžel, Jurij
AU - Abu Arisha, Muhammad
AU - Paul, Stephane
AU - Rocha, Catia
AU - Ben Shatach, Zohar
AU - Abitbol, Chaya Mushka
AU - Haj Natour, Ola
AU - Selinger, Limor
AU - Yavzori, Miri
AU - Fudim, Ella
AU - Picard, Orit
AU - Shoval, Irit
AU - Eliakim, Rami
AU - Kopylov, Uri
AU - Magro, Fernando
AU - Roblin, Xavier
AU - Chowers, Yehuda
AU - Drobne, David
AU - Lukas, Milan
AU - Ben Horin, Shomron
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn's and Colitis Organisation. All rights reserved. For permissions, please email: [email protected].
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
KW - IBD
KW - Vedolizumab
KW - clinical outcome
KW - immunology
KW - pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85117915313&partnerID=8YFLogxK
U2 - 10.1093/ecco-jcc/jjab067
DO - 10.1093/ecco-jcc/jjab067
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C2 - 33837762
AN - SCOPUS:85117915313
SN - 1873-9946
VL - 15
SP - 1707
EP - 1719
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 10
ER -
