Background

Loss of response (LOR) to infliximab (IFX) remains a challenge in routine management of IBD patients. We evaluated IFX high-resolution pharmacokinetics (PK) during induction with intermediate and peak PK levels.

Methods

This is a prospective, multicentre (n = 9), interventional study approved by EC (P2017/484). Fourteen blood samples were collected per patient from baseline to week 30. All patients were IFX naïve with active disease according to clinical, biological and endoscopy criteria. The primary outcome evaluated the inter-individual variability of IFX PK during induction and correlation with remission at week 30. In addition to trough levels (TLs), intermediate (ILs) and peak levels (PLs) were also measured and defined as drug level between two infusions and drug level early on after infusion (+2h), respectively. Remission was defined as having a Harvey Bradshaw Index (HBI) ≤ 4 and C-Reactive Protein (CRP) ≤5 for Crohn’s disease (CD), and as a clinical Mayo score ≤2 and faecal calprotectin <250 µg/g for ulcerative colitis (UC). IFX samples were measured by ELISA (Apdia) while a drug-tolerant affinity capture elution anti-infliximab assay was used to measure anti-infliximab antibodies (ATI) at weeks 6, 22 and 30.

Results

Demographic and baseline data of the study population are presented in Table 1.Among the 62 patients enrolled, 33.9% of patients (n = 21/62) were in remission at week 30. Eight patients dropped out due to disease worsening. Median TLs at week 6 were higher among patients in clinical remission at week 30 (p = 0.02) confirming previous observations. However, ILs at day 3 as well as PLs after the third infusion were also significantly higher in patients in clinical remission at week 30 (Figure 1a–c).ATI were detected as soon as week 6. At week 2, infliximab levels were significantly lower among patients in which ATI developed at a later time point (p = 0.006) and this observation was confirmed when measuring ILs at day 17 (p = 0.002), TLs at week 6 (p = 0.002) and ILs at week 10 (p = 0.001).

Conclusion

This multicentre prospective study demonstrates that intermediate levels as early as day 3 predict remission at week 30 in IBD patients. Low IFX levels during induction were correlated to future ATI development. PK modelling may allow to better select patients early on for sustained remission with infliximab.

中文翻译：

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P362克罗恩病和溃疡性结肠炎（PACIFIC）诱导期间英夫利昔单抗的药物动力学的前瞻性研究

背景

对英夫利昔单抗（IFX）的反应丧失（LOR）仍是IBD患者常规治疗中的一个挑战。我们评估了诱导过程中具有中间和峰值PK水平的IFX高分辨率药代动力学（PK）。

方法

这是EC批准的一项前瞻性，多中心（n = 9）干预性研究（P2017 / 484）。从基线到第30周，每位患者采集14份血样。根据临床，生物学和内窥镜检查标准，所有患者均未患有活动性疾病的IFX。主要结果评估了诱导期间IFX PK的个体间差异以及与第30周缓解的相关性。除了谷值（TL），中间值（IL）和峰值水平（PL）外，还测量并将其定义为分别在输注后早期（+ 2h）进行两次输注和药物水平。克罗恩病（CD）的缓解定义为Harvey Bradshaw指数（HBI）≤4，C反应蛋白（CRP）≤5，溃疡性结肠炎的临床Mayo评分≤2，粪便钙卫蛋白<250 µg / g （UC）。

结果

表1列出了研究人群的人口统计学和基线数据。在入组的62名患者中，有30.3.9％的患者（n = 21/62）在第30周时缓解。八名患者由于疾病恶化而退学。在第30周临床缓解的患者中，第6周的中位TL更高（p = 0.02），这证实了先前的观察结果。但是，第30周临床缓解的患者在第3天的ILs和第三次输注后的PLs也显着升高（图1a–c）。在第6周就检测到ATI。在第2周，英夫利昔单抗水平显着升高在ATI在较晚时间点发展的患者中更低（p = 0.006），并且在测量第17天的IL（p = 0.002），第6周的TL（p = 0.002）和第10周的ILs（p = 0.001）。

结论

这项多中心前瞻性研究表明，早在第3天的中间水平就可以预测IBD患者在第30周的缓解。诱导期间IFX的低水平与未来ATI的发展有关。PK模型可以更好地选择英夫利昔单抗持续缓解的患者。