Infliximab Exposure-Response Relationship and Thresholds Associated With Endoscopic Healing in Patients With Ulcerative Colitis
Infliximab Exposure-Response Relationship and Thresholds Associated With Endoscopic Healing in Patients With Ulcerative Colitis
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DOI：
10.1016/j.cgh.2018.10.036
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发表时间：
2019-08-01
影响因子：
12.6
通讯作者：
Sandborn, William J.
中科院分区：
文献类型：
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作者：
Vande Casteele, Niels;Jeyarajah, Jenny;Sandborn, William J.
背景与目的：治疗药物监测可用于溃疡性结肠炎（UC）患者英夫利西单抗治疗的个性化，尽管与内镜愈合相关的暴露阈值尚不确定。我们的目的是确定在诱导和维持治疗UC患者的内镜结果与英夫利西单抗浓度阈值。方法：我们分析了484例活动性UC患者的数据，包括在2个随机对照试验英夫利西单抗与安慰剂。从第0、8和30周获得马约内镜评分（MES）。使用二室群体药代动力学模型计算基线时英夫利西单抗的清除率。我们检验了基线英夫利西单抗清除率和第8周MES之间的线性趋势。受试者工作曲线分析确定了英夫利西单抗清除率和浓度阈值，其中最大约登指数对应于第8周MES为0或≤ 34.9 μ g/mL，与第14周MES为≤ 5.1 μ g/ mL的第8周相关，第30周>= 2.3 μ g/ mL与第30周MES为≤ 6.7 μ g/ mL相关。第14周>= 3.8 μ g/ mL和第30周>= 3.8 μ g/ mL与第30周MES为0相关。结论：英夫利西单抗的基线清除率和诱导期及维持期英夫利西单抗治疗期间的药物浓度与短期和长期内镜愈合相关。需要基于这些参数进行个体化给药的干预性研究，以显示改善的患者结局。
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.METHODS: 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 = 34.9 mu g/mL at week 8 were associated with a week 8 MES of = 5.1 mu g/ mL at week 14 and >= 2.3 mu g/ mL at week 30 were associated with a week 30 MES of = 6.7 mu g/ mL at week 14 and >= 3.8 mu g/ mL at week 30 were associated with a week 30 MES of 0.CONCLUSIONS: 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.