Portal de investigação
Dose optimisation for Loss of Response to Vedolizumab - Pharmacokinetics and Immune Mechanisms
Autores da FMUP
Participantes de fora da FMUP
- Ungar, B
- Malickova, K
- Hanzel, J
- Abu Arisha, M
- Paul, S
- Rocha, C
- Ben Shatach, Z
- Abitbol, CM
- Natour, OH
- Selinger, L
- Yavzori, M
- Fudim, E
- Picard, O
- Shoval, I
- Eliakim, R
- Kopylov, U
- Roblin, X
- Chowers, Y
- Drobne, D
- Lukas, M
- Ben Horin, S
Unidades de investigação
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, alpha 4 beta 7 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 alpha 4 beta 7 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 alpha 4 beta 7 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 alpha 4 beta 7 receptors of two origins: non-internalised and newly generated alpha 4 beta 7, 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.
Dados da publicação
- ISSN/ISSNe:
- 1873-9946, 1876-4479
- Tipo:
- Article
- Páginas:
- 1707-1719
- PubMed:
- 33837762
- Link para outro recurso:
- www.scopus.com
JOURNAL OF CROHNS & COLITIS Oxford University Press
Citações Recebidas na Web of Science: 11
Citações Recebidas na Scopus: 25
Documentos
- Não há documentos
Filiações
Keywords
- Vedolizumab; IBD; pharmacokinetics; immunology; clinical outcome
Financiamento
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