Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Clin Gastroenterol Hepatol. 2023 May;21(5):1338-1347. doi: 10.1016/j.cgh.2022.08.016. Epub 2022 Aug 27.
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.
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.
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).
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.
gov identifier: NCT02799615.
本研究旨在建立儿童急性重度溃疡性结肠炎（ASUC）患者英夫利昔单抗（IFX）的药代动力学（PK）模型，并评估 PK 参数（包括药物暴露）与临床反应之间的关联。
我们进行了一项多中心前瞻性队列研究，纳入了接受 IFX 治疗的 ASUC 或未分类 IBD 的住院患儿。使用 26 周的 IFX 血清浓度来建立 PK 模型。我们检测了 PK 参数估计值与第 7 天临床反应、第 8 周临床缓解、第 26 周无皮质激素临床缓解（使用儿童溃疡性结肠炎活动指数）和无结肠切除生存之间的相关性。
38 名参与者接受了 IFX 治疗（中位数初始剂量为 9.9mg/kg）。第 7 天临床反应、第 8 周临床缓解和第 26 周无皮质激素临床缓解的发生率分别为 71%、55%和 43%。白蛋白、C 反应蛋白、白细胞计数、血小板计数、体重和 IFX 抗体是纳入 PK 模型的重要协变量。第 26 周未缓解者的 IFX 清除率快于缓解者（P=0.013）。然而，临床反应组之间的累积 IFX 暴露无差异。第 26 周和第 2 年分别有 1 例（2.7%）和 4 例（10.8%）参与者接受了结肠切除术。第 3 天 IFX 清除率＞0.02L/h 与结肠切除术相关（风险比，58.2；95%置信区间，6.0-568.6；P＜0.001）。
在对儿童 ASUC 进行中位数高于标签剂量的 IFX 治疗时，基线时较快的 IFX CL 与结肠切除术相关，而在第 26 周时与缺乏 CSF-CR 相关。IFX 暴露不能预测临床结局。更高的 IFX 剂量可能足以优化儿童 ASUC 的早期结局。需要更大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局。
gov 标识符：NCT02799615。
