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Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis
Clinical Gastroenterology and Hepatology ( IF 12.6 ) Pub Date : 2022-08-27 , DOI: 10.1016/j.cgh.2022.08.016
Kaitlin G Whaley 1 , Ye Xiong 2 , Rebekah Karns 3 , Jeffrey S Hyams 4 , Subra Kugathasan 5 , Brendan M Boyle 6 , Thomas D Walters 7 , Judith Kelsen 8 , Neal LeLeiko 9 , Jason Shapiro 10 , Amanda Waddell 3 , Sejal Fox 3 , Ramona Bezold 3 , Stephanie Bruns 3 , Robin Widing 11 , Yael Haberman 12 , Margaret H Collins 13 , Tomoyuki Mizuno 14 , Phillip Minar 1 , Geert R D'Haens 15 , Lee A Denson 1 , Alexander A Vinks 14 , Michael J Rosen 16
Affiliation  

Background & aims

We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response.

Methods

We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index), and colectomy-free survival.

Results

Thirty-eight participants received IFX (median initial dose, 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P = .013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and 4 (10.8%) participants underwent colectomy by week 26 and 2 years, respectively. Day 3 IFX clearance >0.02 L/h was associated with colectomy (hazard ratio, 58.2; 95% confidence interval, 6.0–568.6; P < .001).

Conclusions

At median higher-than-label IFX dosing for pediatric ASUC, baseline faster IFX CL was associated with colectomy and at week 26 with lack of CSF-CR. IFX exposure was not predictive of clinical outcomes. Higher IFX dosing may sufficiently optimize early outcomes in pediatric ASUC. Larger studies are warranted to determine whether sustained intensification can overcome rapid clearance and improve later outcomes. ClinicalTrials.gov identifier: NCT02799615.



中文翻译:

英夫利昔单抗在小儿急性重度溃疡性结肠炎中的药代动力学和治疗反应的多中心队列研究

背景与目标

我们旨在模拟儿科急性重症溃疡性结肠炎 (ASUC) 中的英夫利昔单抗 (IFX) 药代动力学 (PK),并评估 PK 参数(包括药物暴露)与临床反应之间的关联。

方法

我们研究了一项针对 ASUC 或 IBD 未分类的住院儿童启动 IFX 的多中心前瞻性队列。使用超过 26 周的系列 IFX 血清浓度来开发 PK 模型。我们测试了 PK 参数估计值与第 7 天临床反应、第 8 周临床缓解、第 26 周无皮质类固醇临床缓解 (CSF-CR)(使用小儿溃疡性结肠炎活动指数)和无结肠切除术生存期之间的关联。

结果

38 名参与者接受了 IFX(中位初始剂量,9.9 mg/kg)。第 7 天临床反应、第 8 周临床缓解和第 26 周 CSF-CR 的发生率分别为 71%、55% 和 43%。白蛋白、C 反应蛋白、白细胞计数、血小板、体重和 IFX 抗体是纳入 PK 模型的重要协变量。第 26 周非汇款者表现出比汇款者更快的 IFX 清除 ( P  = .013)。然而,累积的 IFX 暴露在临床反应组之间没有差异。1 名 (2.7%) 和 4 名 (10.8%) 参与者分别在第 26 周和 2 年时接受了结肠切除术。第 3 天 IFX 清除率 >0.02 L/h 与结肠切除术相关(风险比,58.2;95% 置信区间,6.0–568.6;P < .001)。

结论

在儿科 ASUC 的中位高于标签的 IFX 剂量下,基线更快的 IFX CL 与结肠切除术相关,并且在第 26 周时与缺乏 CSF-CR 相关。IFX 暴露不能预测临床结果。更高的 IFX 剂量可能足以优化儿科 ASUC 的早期结果。需要更大规模的研究来确定持续强化是否可以克服快速清除并改善后期结果。ClinicalTrials.gov标识符:NCT02799615。

更新日期:2022-08-27
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