Improved Population Pharmacokinetic Model for Predicting Optimized Infliximab Exposure in Pediatric Inflammatory Bowel Disease.
- 作者列表："Bauman LE","Xiong Y","Mizuno T","Minar P","Fukuda T","Dong M","Rosen MJ","Vinks AA
BACKGROUND:Many pediatric patients with inflammatory bowel disease (IBD) lose response to infliximab (IFX) within the first year, and achieving a minimal target IFX trough concentration is associated with higher remission rates and longer durability. Population pharmacokinetic (PK) modeling can predict trough concentrations for individualized dosing. The object of this study was to refine a population PK model that accurately predicts individual IFX exposure during maintenance therapy using longitudinal real-practice data. METHODS:We exported data from the electronic health records of pediatric patients with IBD treated with originator IFX at a single center between January 2011 and March 2017. Subjects were divided into discovery and validation cohorts. A population PK model was built and then validated. RESULTS:We identified 228 pediatric patients with IBD who received IFX and had at least 1 drug concentration measured, including 135 and 93 patients in the discovery and validation cohorts, respectively. Weight, albumin, antibodies to IFX (ATI) detected by a drug-tolerant assay, and erythrocyte sedimentation rate (ESR) were identified as covariates significantly associated with IFX clearance and incorporated into the model. The model exhibited high accuracy for predicting target IFX trough concentrations with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% confidence interval [CI], 0.81-0.91) for population-based predictions without prior drug-level input. Accuracy increased further for individual-based predictions when prior drug levels were known, with an AUROC of 0.93 (95% CI, 0.90-0.97). CONCLUSIONS:A population PK model utilizing weight, albumin, ordinal drug-tolerant ATI, and ESR accurately predicts IFX trough concentrations during maintenance therapy in real-practice pediatric patients with IBD. This model, which incorporates dynamic clinical information, could be used for individualized dosing decisions to increase response durability.
背景: 许多患有炎症性肠病 (IBD) 的儿童患者在第一年内对英夫利昔单抗 (IFX) 失去反应, 达到最低目标 IFX 谷浓度与较高的缓解率和较长的持久性相关。群体药代动力学 (PK) 建模可以预测个体化给药的谷浓度。本研究的目的是使用纵向真实实践数据精确预测维持治疗期间个体 IFX 暴露的人群 PK 模型。 方法: 我们从 2011年1月至 2017年3月间在单中心接受 IFX 治疗的 IBD 患儿的电子健康档案中导出数据。将受试者分为发现和验证队列。构建了种群 PK 模型，并进行了验证。 结果: 我们确定了 228 例接受 IFX 并测量了至少 1 种药物浓度的 IBD 儿童患者，其中发现队列和验证队列分别为 135 例和 93 例患者。通过药物耐受性试验检测的体重、白蛋白、 IFX 抗体 (ATI) 和红细胞沉降率 (ESR) 被确定为与 IFX 清除率显著相关的协变量，并纳入模型。该模型对预测目标 IFX 谷浓度具有较高的准确性，受试者工作特征曲线 (AUROC) 下面积为 0.86 (95% 置信区间 [CI]，0.81-0.91) 对于没有先前药物水平输入的基于人群的预测。当已知既往药物水平时，基于个体的预测的准确性进一步提高，AUROC 为 0.93 (95% CI，0.90-0.97)。 结论: 利用体重、白蛋白、有序药物耐受性 ATI 和 ESR 的群体 PK 模型可准确预测真实实践的 IBD 儿科患者维持治疗期间的 IFX 谷浓度。该模型结合了动态临床信息，可用于个体化给药决策，以增加反应持久性。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.