van Hoeve Karen, Seyed Tabib Nasim Sadat, Dreesen Erwin, Tops Sophie, Hoffman Ilse, Gils Ann, Ferrante Marc, Vermeire Séverine
Department of Pediatric Gastroenterology & Hepatology & Nutrition, University Hospitals Leuven, KU Leuven, Leuven, Belgium; TARGID, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium.
TARGID, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium.
J Pediatr. 2022 Jan;240:150-157.e4. doi: 10.1016/j.jpeds.2021.08.079. Epub 2021 Sep 3.
To study infliximab (IFX) pharmacokinetics in children with inflammatory bowel disease (IBD) during induction therapy to predict outcome and explore if other covariates influenced outcome.
All children with IBD starting IFX therapy (5 mg/kg at weeks 0, 2, 6, and 12) for active luminal disease from May 2017 to May 2019 were included and followed prospectively. Patients were sampled at multiple timepoints during induction (trough concentrations and peak concentration at weeks 0, 2, 6, and 12, and intermediate concentration at weeks 1-4). IFX concentrations and cumulative drug exposure were correlated with outcome at 6 months. Endoscopic remission was defined as Simple Endoscopic Score for Crohn's Disease of <3 or Mayo endoscopic subscore of 0, and deep remission as endoscopic with clinical remission (Pediatric Ulcerative Colitis Activity Index/Pediatric Crohn's Disease Activity Index of <10).
There were 252 serum induction concentrations obtained from 32 patients (81% on concomitant thiopurines). Children in endoscopic remission (all in deep remission) at 6 months had significantly higher drug concentrations from week 4 onward. A receiver operating characteristics curve analysis identified IFX trough concentrations at week 12 of ≥5.0 μg/mL and area under the curve at weeks 0-12 of ≥4056.0 μg∗day/mL as the minimal target to achieve endoscopic remission at 6 months (area under the receiver operating characteristics curve, 0.796 [95% CI, 0.62-0.97] and area under the receiver operating characteristics curve, 0.778 [95% CI, 0.61-0.94], respectively). In addition, our findings suggest that proteomic analysis may help to understand IFX response.
Higher IFX exposure during induction therapy in pediatric patients with IBD is associated with significantly better endoscopic and deep remission rates at 6 months. Drug concentrations differentiate remitters from nonremitters from week 4 after induction onward.
研究英夫利昔单抗（IFX）在炎症性肠病（IBD）儿童诱导治疗期间的药代动力学，以预测治疗结果，并探讨其他协变量是否会影响治疗结果。
纳入2017年5月至2019年5月期间所有开始接受IFX治疗（在第0、2、6和12周给予5mg/kg）以治疗活动性肠腔疾病的IBD儿童，并进行前瞻性随访。在诱导治疗期间的多个时间点对患者进行采样（第0、2、6和12周的谷浓度和峰浓度，以及第1 - 4周的中间浓度）。IFX浓度和累积药物暴露与6个月时的治疗结果相关。内镜缓解定义为克罗恩病简单内镜评分<3或梅奥内镜亚评分0，深度缓解定义为内镜缓解且临床缓解（小儿溃疡性结肠炎活动指数/小儿克罗恩病活动指数<10）。
从32例患者中获得了252个血清诱导浓度（81%患者同时使用硫唑嘌呤）。6个月时达到内镜缓解（均为深度缓解）的儿童从第4周起药物浓度显著更高。接受者操作特征曲线分析确定，第12周IFX谷浓度≥5.0μg/mL以及第0 - 12周曲线下面积≥4056.0μg∗天/mL是6个月时实现内镜缓解的最低目标（接受者操作特征曲线下面积分别为0.796 [95% CI，0.62 - 0.97]和0.778 [95% CI，0.61 - 0.94]）。此外，我们的研究结果表明蛋白质组学分析可能有助于理解IFX反应。
IBD儿科患者诱导治疗期间较高的IFX暴露与6个月时显著更好的内镜缓解率和深度缓解率相关。诱导治疗后第4周起，药物浓度可区分缓解者与未缓解者。
