Department of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, California; Robarts Clinical Trials, Inc, London, Ontario, Canada.
Robarts Clinical Trials, Inc, London, Ontario, Canada.
Clin Gastroenterol Hepatol. 2019 Aug;17(9):1814-1821.e1. doi: 10.1016/j.cgh.2018.10.036. Epub 2018 Oct 26.
BACKGROUND & AIMS: Therapeutic drug monitoring might be used to personalize infliximab treatment of patients with ulcerative colitis (UC), although exposure thresholds associated with endoscopic healing are uncertain. We aimed to determine infliximab concentration thresholds associated with endoscopic outcomes during induction and maintenance therapy for patients with UC.
We analyzed data from 484 patients with active UC included in 2 randomized controlled trials of infliximab vs placebo. Mayo endoscopic scores (MES) were available from weeks 0, 8, and 30. A 2-compartment population pharmacokinetic model was used to calculate infliximab clearance at baseline. We tested the linear trend between baseline infliximab clearance and MES at week 8. Receiver operating curve analysis identified infliximab clearance and concentration thresholds with a maximum Youden index corresponding to a MES of 0 or ≤1.
We found a linear relationship between baseline infliximab clearance and week 8 MES (P < .001); a threshold of <0.397 L/d was associated with week 8 MES ≤1. Infliximab concentrations ≥18.6 μg/mL at week 2, ≥10.6 μg/mL at week 6, and ≥34.9 μg/mL at week 8 were associated with a week 8 MES of ≤1. Infliximab concentrations ≥5.1 μg/mL at week 14 and ≥2.3 μg/mL at week 30 were associated with a week 30 MES of ≤1. Infliximab concentrations ≥6.7 μg/mL at week 14 and ≥3.8 μg/mL at week 30 were associated with a week 30 MES of 0.
Baseline clearance of infliximab and drug concentrations during induction and maintenance infliximab therapy are associated with short- and long-term endoscopic healing. Interventional studies that incorporate individualized dosing based on these parameters are required to show improved patient outcomes.
治疗药物监测可能用于溃疡性结肠炎（UC）患者的英夫利昔单抗个体化治疗，尽管与内镜愈合相关的暴露阈值尚不确定。我们旨在确定与 UC 患者诱导和维持治疗期间内镜结局相关的英夫利昔单抗浓度阈值。
我们分析了两项英夫利昔单抗与安慰剂对照的随机对照试验中纳入的 484 例活动期 UC 患者的数据。在 0 周、8 周和 30 周时可获得 Mayo 内镜评分（MES）。采用两室群体药代动力学模型计算基线时英夫利昔单抗清除率。我们测试了基线时英夫利昔单抗清除率与第 8 周 MES 之间的线性趋势。受试者工作特征曲线分析确定了与 MES 为 0 或 ≤1 对应的最大 Youden 指数的英夫利昔单抗清除率和浓度阈值。
我们发现基线英夫利昔单抗清除率与第 8 周 MES 之间存在线性关系（P <.001）；第 8 周 MES ≤1 与清除率 <0.397 L/d 相关。第 2 周时英夫利昔单抗浓度≥18.6 μg/mL、第 6 周时≥10.6 μg/mL、第 8 周时≥34.9 μg/mL 与第 8 周 MES ≤1 相关。第 14 周时英夫利昔单抗浓度≥5.1 μg/mL、第 30 周时≥2.3 μg/mL 与第 30 周 MES ≤1 相关。第 14 周时英夫利昔单抗浓度≥6.7 μg/mL、第 30 周时≥3.8 μg/mL 与第 30 周 MES=0 相关。
英夫利昔单抗的基线清除率和诱导及维持英夫利昔单抗治疗期间的药物浓度与短期和长期内镜愈合相关。需要进行纳入这些参数的个体化给药的干预性研究，以显示改善患者结局。
