Biologics Clinical Pharmacology, Biostatistics, Immunology, Janssen Research & Development, LLC, Spring House, Pennsylvania.
Division of Gastroenterology, University of California San Diego, La Jolla, California.
Gastroenterology. 2014 Dec;147(6):1296-1307.e5. doi: 10.1053/j.gastro.2014.08.035. Epub 2014 Aug 28.
BACKGROUND & AIMS: We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis.
We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response.
Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients.
Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.
我们分析了在积极溃疡性结肠炎试验（ACT-1 和 ACT-2）期间收集的数据，以评估成人中度至重度溃疡性结肠炎患者血清中英夫利昔单抗浓度与结局之间的关系。
我们比较了 728 例中度至重度活动溃疡性结肠炎患者的血清英夫利昔单抗浓度与结局，这些患者参加了 ACT-1 或 ACT-2；仅在第 8、30 和 54 周（仅 ACT-1）收集疗效数据。使用趋势、逻辑回归和接收者操作特征曲线分析评估英夫利昔单抗血清浓度与疗效结局之间的关系。我们还评估了影响暴露与反应关系的因素。
在具有临床反应、黏膜愈合和/或临床缓解的患者中，第 8、30 和/或 54 周时的英夫利昔单抗血清浓度中位数明显高于未达到这些反应标准的患者。在这些时间点，英夫利昔单抗血清浓度四分位数与疗效之间存在统计学显著关系（P<.01）。在最低四分位数的患者中，英夫利昔单抗治疗的有效率较低，这些患者的血清白蛋白水平较低，抗英夫利昔单抗抗体的发生率较高，而其他四分位数的患者则较低。尽管英夫利昔单抗暴露与反应之间的关系在患者之间存在差异，但诱导治疗第 8 周时约 41 μg/mL 的英夫利昔单抗血清浓度和维持治疗期间稳态时 3.7 μg/mL 的英夫利昔单抗血清浓度可使患者获得最佳结局。
血清英夫利昔单抗浓度与中度至重度溃疡性结肠炎患者的疗效相关；然而，复杂的因素决定了该药物暴露与反应之间的关系。在这些数据可纳入患者管理策略之前，应进行前瞻性评估测量英夫利昔单抗血清浓度的价值。临床试验.gov 编号：NCT00036439 和 NCT00096655。
