Background

Multiple studies have reported the association between vedolizumab serum concentrations and endoscopic outcomes in patients with ulcerative colitis (UC). However, little is known about drug consumption in tissue and the relationship with mucosal inflammation. This study aimed to investigate vedolizumab concentrations in the tissue of UC patients and the correlation with their inflammatory state and serum levels.

Methods

A paired serum sample and colonic mucosal biopsy were collected in 36 UC patients at week 14 of vedolizumab treatment. In non-responders, defined as a Mayo endoscopic subscore of ≥2, inflamed colonic biopsies were taken in the sigmoid around 20–30 cm from the anal verge. In responders, defined as a Mayo endoscopic subscore ≤ 1, a biopsy was taken in a macroscopically uninflamed area at the same location. Biopsies were lysed by the addition of 10 μl lysis buffer (50 mM Tris, 0.1% Triton X-100 and 100 mM NaCl) per mg tissue and vortexed every 5 min during 1 h. Total protein content was measured and normalised to 3 mg/ml before analysis of the vedolizumab concentration using an in-house developed ELISA. Results are expressed as µg vedolizumab/mg total protein content.

Results

A positive correlation was observed between vedolizumab concentrations in tissue and serum (Spearman r = 0.8447, p < 0.0001), both in inflamed (r = 0.8609, p <0.0001, n = 16) and uninflamed tissue (r = 0.7925, p <0.0001, n = 20). The median tissue vedolizumab concentration in patients with Mayo endoscopic subscore 0, 1, 2 and 3 were 0.120, 0.074, 0.062 and 0.064 μg/mg, respectively (p < 0.01, see figure), indicating that tissue drug levels inversely correlate with the severity of inflammation. Vedolizumab tissue concentrations were significantly lower in non-responders compared with responders (0.064 vs. 0.112 μg/mg, p <0.05). Moreover, patients achieving Mayo endoscopic subscore 0 had significantly higher vedolizumab levels in colonic tissue compared with patients not achieving this outcome (0.120 vs. 0.065 μg/mg, p <0.02). Interestingly, a trend was observed towards higher serum-to-tissue ratios of vedolizumab in non-responders compared with responders (p = 0.0523). This finding suggests that if two patients have the same serum vedolizumab concentration, the patient with mucosal inflammation is more likely to have lower tissue levels than the patient with no or limited inflammation.

Conclusion

Vedolizumab concentrations in colonic mucosal tissue of UC patients inversely correlate with the severity of inflammation. As the serum-to-tissue ratio of vedolizumab is numerically higher in non-responders compared with responders, the relative distribution of vedolizumab in serum and tissue might be more important than the drug concentration alone.

中文翻译：

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P464溃疡性结肠炎患者结肠黏膜组织中维多珠单抗的浓度与炎症的严重程度呈负相关

背景

多项研究报告了溃疡性结肠炎（UC）患者中维多珠单抗血清浓度与内镜结果之间的相关性。但是，对于组织中的药物消耗以及与粘膜炎症的关系知之甚少。这项研究旨在调查维多珠单抗在UC患者组织中的浓度及其与炎症状态和血清水平的相关性。

方法

在维多珠单抗治疗的第14周时，在36名UC患者中收集了配对的血清样本和结肠黏膜活检。在无反应者中定义为Mayo内镜评分≥2，在距肛门边缘约20-30 cm的乙状结肠中进行了发炎的结肠活检。在定义为Mayo内镜评分≤1的响应者中，在同一位置的肉眼未发炎的区域进行活检。通过向每毫克组织中添加10μl裂解缓冲液（50 mM Tris，0.1％Triton X-100和100 mM NaCl）裂解活检组织，并在5小时内每5分钟涡旋振荡一次。在使用内部开发的ELISA分析维多珠单抗浓度之前，测量总蛋白质含量并将其标准化为3 mg / ml。结果表示为微克维多珠单抗/毫克总蛋白含量。

结果

在发炎（r = 0.8609，p <0.0001，n = 16）和未发炎的组织（r = 0.7925，p <0.0001）中，组织和血清中的维多珠单抗浓度（Spearman r = 0.8447，p <0.0001）之间观察到正相关。 ，n = 20）。Mayo内镜下评分0、1、2和3的患者组织维多珠单抗的中位浓度分别为0.120、0.074、0.062和0.064μg/ mg（p <0.01，见图），表明组织药物水平与严重程度呈负相关炎症。与反应者相比，非反应者中维多珠单抗组织浓度显着降低（0.064 vs. 0.112μg/ mg，p <0.05）。此外，与未达到该结果的患者相比，达到Mayo内镜下评分0的患者结肠组织中的维多珠单抗水平明显更高（0.120 vs. 0.065μg/ mg，p <0.02）。有趣的是，观察到无反应者与非反应者相比，维多珠单抗的血清/组织比率更高的趋势（p = 0.0523）。该发现表明，如果两名患者具有相同的血清维多珠单抗浓度，则粘膜炎症患者比无炎症患者或炎症受限患者的组织水平更低。

结论

UC患者结肠粘膜组织中的维多珠单抗浓度与炎症的严重程度成反比。由于非反应者中维多珠单抗的血清/组织比率在数值上高于反应者，因此维多珠单抗在血清和组织中的相对分布可能比单独的药物浓度更为重要。