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
- 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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Citar a publicação
Ungar B,Malickova K,Hanzel J,Abu M,Paul S,Rocha C,Ben Z,Abitbol CM,Natour OH,Selinger L,Yavzori M,Fudim E,Picard O,Shoval I,Eliakim R,Kopylov U,Magro F,Roblin X,Chowers Y,Drobne D,Lukas M,Ben S. Dose optimisation for Loss of Response to Vedolizumab - Pharmacokinetics and Immune Mechanisms. J. Crohn's Colitis. 2021. 15. (10):p. 1707-1719. IF:10,020. (1).
