Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic.
J Crohns Colitis. 2021 Oct 7;15(10):1707-1719. doi: 10.1093/ecco-jcc/jjab067.
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.
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.
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.
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.
关于需要剂量优化的患者中维得利珠单抗药代动力学的真实数据很少。我们旨在研究预优化维得利珠单抗水平是否与治疗结果相关，以及哪些机制解释了这种相关性。
一项多中心观察性研究评估了剂量增加与维得利珠单抗治疗患者的预升级水平相关的结果。随后，在输注日对接受下内窥镜检查的患者的各种细胞亚群上研究了外周血 [PB] 和肠固有层 [LP] 组织上的 α4β7 占据情况。还探索了维得利珠单抗结合的 α4β7 的细胞定位及其对 M1 和 M2 巨噬细胞的影响。
共纳入 161 例炎症性肠病 [IBD] 患者。在 161 例患者中的 129 例/161 例患者在维持治疗中强化治疗[第 14 周开始]，与未缓解患者相比，在随后达到优化后临床、生物标志物和内镜缓解的患者中，预强化低谷水平相当或更高[分别为 p=0.09、0.25、0.04]。在诱导期[第 6 周，n=32]进行剂量优化的患者中也观察到了类似的结果。在免疫亚研究[n=43]中，在 PB T 细胞[p=0.15]、LP T 细胞[ p=0.88]和 PB 嗜酸性粒细胞[p=0.08]上，有黏膜愈合的患者和无黏膜愈合的患者的游离 α4β7 受体相似低。M1 和 M2 巨噬细胞上的整合素受体也被低水平的维得利珠单抗饱和，抗炎细胞因子的分泌没有增加。共定位和解离实验表明，两种来源的膜 α4β7 受体：非内化和新生成的 α4β7，但在非常低的浓度下仍能完全重新结合。
这些结果不支持药代动力学是导致对维得利珠单抗反应丧失的机制，也不支持需要更高的药物浓度来增强维得利珠单抗的免疫作用。较高的预升级水平可能表明清除率较低[疾病较轻]，随后再次获得应答的可能性较高，而与治疗升级无关。
