BACKGROUND & AIMS In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS We performed a post hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease ≥50% from baseline), endoscopic remission (CD endoscopic index of severity, <3), and absence of ulcers at weeks 12 and 54 of infliximab treatment. RESULTS Infliximab trough concentrations greater than 23.1 mg/L at week 2 and greater than 10.0 mg/L at week 6 were associated with endoscopic remission at week 12 (positive predictive values, 72% and 76%; negative predictive values, 65% and 59%, respectively). During maintenance therapy, we found evidence for an exposure-response relationship only after dose escalation; trough concentrations greater than 10.6 mg/L were associated with the absence of ulcers at week 54 (positive predictive value, 49%; negative predictive value, 92%). Low fecal concentrations of calprotectin during therapy were associated with endoscopic response and remission (P < .05). Dose escalations increased trough concentrations of infliximab; persistent increase in fecal concentration of calprotectin, despite dose escalation, was associated with a lack of endoscopic response and remission. A significantly higher proportion of patients with antibodies to infliximab, identified by a drug-tolerant assay, dropped out of the study compared with patients without antibodies (P < .0001). CONCLUSIONS In a post hoc analysis of data from a trial to test the effects of infliximab dose escalation on symptoms, we found that during maintenance therapy, the combination of fecal concentration of calprotectin and trough concentration of infliximab can guide dose adjustment and increase the chances for endoscopic response and remission. ClinicalTrialsRegister.eu EudraCT no: 2011-003038-14.

中文翻译：

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监测钙卫蛋白和英夫利昔单抗的组合可识别克罗恩病黏膜愈合的患者。

背景和目的 在 TAILORIX 试验中，与仅基于症状的克罗恩病 (CD) 患者的剂量递增相比，基于药代动力学（英夫利昔单抗血清浓度）和药效学（生物标志物和症状）监测的英夫利昔单抗剂量递增未显示出任何益处。我们根据内窥镜检查的结果调查了药代动力学和药效学监测的整合是否可用于评估对英夫利昔单抗诱导和维持治疗的反应。方法 我们对纳入一项试验的 CD 患者进行了事后分析，以根据生物标志物和英夫利昔单抗的血清浓度测试英夫利昔单抗剂量递增对症状的影响（研究使用英夫利昔单抗定制治疗活动性克罗恩病试验；n = 122)。我们分析了这项研究的数据，以确定生物标志物浓度和英夫利昔单抗的血清浓度是否与内镜结果相关（n = 116）。主要终点是内镜反应（CD 内镜严重程度指数从基线下降 ≥ 50%）、内镜缓解（CD 内镜严重指数 <3）以及在英夫利昔单抗治疗的第 12 周和第 54 周时没有溃疡。结果 英夫利昔单抗谷浓度在第 2 周大于 23.1 mg/L 和在第 6 周大于 10.0 mg/L 与第 12 周的内镜缓解相关（阳性预测值分别为 72% 和 76%；阴性预测值分别为 65% 和 59 ％， 分别）。在维持治疗期间，我们发现仅在剂量增加后存在暴露-反应关系的证据；谷浓度大于 10。6 mg/L 与第 54 周无溃疡相关（阳性预测值为 49%；阴性预测值为 92%）。治疗期间粪便中低浓度的钙卫蛋白与内镜反应和缓解相关（P < .05）。剂量增加增加了英夫利昔单抗的谷浓度；尽管剂量增加，但粪便中钙卫蛋白浓度的持续增加与内镜反应缺乏和缓解有关。与没有抗体的患者相比，通过药物耐受试验确定的具有英夫利昔单抗抗体的患者退出研究的比例显着更高（P < .0001）。结论 在对一项试验数据进行事后分析以测试英夫利昔单抗剂量递增对症状的影响时，我们发现在维持治疗期间，粪便钙卫蛋白浓度与英夫利昔单抗谷浓度相结合可指导剂量调整，增加内镜反应和缓解的机会。ClinicalTrialsRegister.eu EudraCT 编号：2011-003038-14。