Chung Aaron, Carroll Matthew, Almeida Patricia, Petrova Alexandra, Isaac Daniela, Mould Diane, Wine Eytan, Huynh Hien
Division of Pediatric Gastroenterology, Faculty of Medicine, University of Alberta, Edmonton, Canada.
Projections Research Inc, Phoenixville, USA.
Dig Dis Sci. 2023 May;68(5):1995-2005. doi: 10.1007/s10620-022-07783-3. Epub 2022 Dec 23.
Children with Crohn's disease have lower response rates to infliximab, lower infliximab levels, and higher infliximab clearance on weight-based dosing than adults. We hypothesize infliximab clearance is a predictive of later outcomes on infliximab in children with Crohn's disease.
In this single-center retrospective study, data were collected from charts on diagnosis, anthropometry, routine labs, infliximab therapeutic drug monitoring, infliximab dosing, disease activity, and other treatments. With these data we generated a population pharmacokinetic model using non-linear mixed effects modeling and calculated infliximab clearance for each patient over time. Patients were classified as in remission, responder-only or non-responder at 5, 10 and 16 months. Regression and ROC analyses were used to assess for early predictors of remission and response to infliximab.
Eighty-five subjects were included, with a median follow-up of 22.3 months (IQR 10.1-36.8). Our pharmacokinetic model showed infliximab clearance was positively associated with CRP and weight, while negatively associated with albumin. In regression analyses, early infliximab clearance was the only significant, consistent predictor of remission. A 0.1 L/day increase in infliximab clearance predicted remission with an OR between 0.179 and 0.426. Differences in dosing did not account for differences in outcome. Infliximab clearance alone had moderate predictive accuracy of remission, with an AUC between 0.682 and 0.738.
Early infliximab clearance is strongly associated with remission in children with Crohn's disease. It may be useful as a marker of response in proactive therapeutic drug monitoring to guide early dose optimization and/or changes in treatment for betterment of long-term outcomes.
与成人相比，克罗恩病患儿对英夫利昔单抗的反应率较低，英夫利昔单抗水平较低，且基于体重给药时英夫利昔单抗清除率较高。我们推测英夫利昔单抗清除率可预测克罗恩病患儿使用英夫利昔单抗后的后续结局。
在这项单中心回顾性研究中，从病历中收集了有关诊断、人体测量学、常规实验室检查、英夫利昔单抗治疗药物监测、英夫利昔单抗给药、疾病活动度及其他治疗的数据。利用这些数据，我们采用非线性混合效应模型建立了群体药代动力学模型，并计算了每位患者随时间变化的英夫利昔单抗清除率。在第5、10和16个月时，将患者分类为缓解、仅缓解或未缓解。采用回归分析和ROC分析评估缓解及对英夫利昔单抗反应的早期预测因素。
纳入85名受试者，中位随访时间为22.3个月（四分位间距10.1 - 36.8）。我们的药代动力学模型显示，英夫利昔单抗清除率与CRP和体重呈正相关，而与白蛋白呈负相关。在回归分析中，早期英夫利昔单抗清除率是缓解的唯一显著、一致的预测因素。英夫利昔单抗清除率每增加0.1 L/天，缓解的OR值在0.179至0.426之间。给药差异并不能解释结局差异。仅英夫利昔单抗清除率对缓解具有中等预测准确性，AUC在0.682至0.738之间。
早期英夫利昔单抗清除率与克罗恩病患儿的缓解密切相关。在积极的治疗药物监测中，它可能作为反应标志物，以指导早期剂量优化和/或改变治疗方案，从而改善长期结局。
