Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Uvalu 84, 150 06, Prague 5, Czech Republic.
Laboratory of Growth Regulators, Palacky University Olomouc and Institute of Experimental Botany AS CR, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
Paediatr Drugs. 2021 Mar;23(2):183-194. doi: 10.1007/s40272-021-00439-1. Epub 2021 Mar 11.
The additional value of azathioprine concomitant treatment on infliximab pharmacokinetics in children is not well described yet.
In the present study, we aimed to describe the relationship between thiopurine metabolite levels, infliximab trough levels, anti-IFX antibody formation, and clinical and laboratory markers of disease activity in pediatric patients with Crohn's disease, and to assess non-adherence.
Data were collected prospectively during repeated visits from pediatric patients followed for Crohn's disease in two Czech pediatric inflammatory bowel disease centers between January 2016 and June 2017. Thiopurine metabolites (6-thioguanine and 6-methylmercaptopurine) were measured by high-performance liquid chromatography. Infliximab trough levels and anti-IFX antibody serum levels were measured routinely by ELISA. The risk of loss of response to infliximab therapy was also assessed.
A significant association between infliximab serum levels and 6-thioguanine erythrocyte levels was observed when tested as categorical variables (63 patients, 321 observations). To predict infliximab levels > 5 µg/mL, we propose a 6-thioguanine cutoff of 278 pmol/8 × 10 erythrocytes (sensitivity, 0.799; specificity, 0.347). A higher loss-of-response-to-infliximab rate (tested in a subgroup of 51 patients) was observed in patients with undetectable 6-thioguanine levels than in those with detectable levels (p = 0.026). Non-adherence to azathioprine therapy was suspected in 20% of patients.
Thiopurine metabolite monitoring in pediatric patients with Crohn's disease is useful when optimizing combination therapy. Pediatric patients with undetectable 6-thioguanine levels are more likely to lose response to infliximab therapy. When targeting optimal infliximab levels, the 6-thioguanine cutoff levels in children appear to be higher than in adults.
目前尚未充分描述在儿童中合用巯嘌呤类药物对英夫利昔单抗药代动力学的额外价值。
本研究旨在描述在捷克两家儿科炎症性肠病中心接受英夫利昔单抗治疗的儿童克罗恩病患者中，硫代嘌呤代谢物水平、英夫利昔单抗谷浓度、抗英夫利昔单抗抗体形成与疾病活动的临床和实验室标志物之间的关系，并评估不依从性。
2016 年 1 月至 2017 年 6 月，前瞻性收集了在这两家捷克儿科炎症性肠病中心接受克罗恩病治疗的儿科患者重复就诊时的数据。采用高效液相色谱法检测硫代嘌呤代谢物（6-硫代鸟嘌呤和 6-甲基巯基嘌呤）。常规采用酶联免疫吸附法检测英夫利昔单抗谷浓度和抗英夫利昔单抗抗体血清浓度。还评估了英夫利昔单抗治疗失效的风险。
当作为分类变量进行检验时，观察到英夫利昔单抗血清水平与红细胞内 6-硫代鸟嘌呤水平之间存在显著关联（63 例患者，321 次观察）。为了预测英夫利昔单抗水平＞5μg/ml，我们提出红细胞内 6-硫代鸟嘌呤的截断值为 278pmol/8×10红细胞（敏感性为 0.799，特异性为 0.347）。在亚组 51 例患者中观察到，6-硫代鸟嘌呤水平不可检测的患者的英夫利昔单抗失效率更高（p=0.026）。怀疑有 20%的患者未依从巯嘌呤类药物治疗。
在优化联合治疗时，对患有克罗恩病的儿童进行硫嘌呤代谢物监测是有用的。6-硫代鸟嘌呤水平不可检测的儿科患者更有可能对英夫利昔单抗治疗失去反应。在针对最佳英夫利昔单抗水平时，儿童的 6-硫代鸟嘌呤截断值似乎高于成人。
