Department of Pharmacy, Hospital Universitari de Bellvitge-HUB, Pharmacotherapy, Pharmacogenetics and Pharmaceutical Technology Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat.
Department of Gastroenterology, Hospital Universitari de Bellvitge-HUB, L'Hospitalet de Llobregat.
Ther Drug Monit. 2020 Feb;42(1):102-110. doi: 10.1097/FTD.0000000000000669.
Treating patients based on a treat-to-trough approach has been shown to be a cost-effective strategy for inflammatory bowel disease (IBD) patients who have become unresponsive to infliximab (IFX). However, the documented evidence for this is limited, and some controversy remains regarding the use of routine proactive therapeutic drug monitoring (TDM). To support routine TDM of IFX and regimen optimization in IBD patients, more in-depth knowledge of the covariates that affect the pharmacokinetic (PK) variability of IFX is needed. The aim of this study was to identify the characteristics of the patient, disease, and treatments that influence IFX PK and exposure in our cohort of IBD patients using a repeated-measures design.
We performed a prospective observational study of adult IBD patients who received IFX between July 2013 and March 2017. We obtained repeated IFX trough concentration (Cmin) measurements and implemented a previously described population pharmacokinetic model to estimate individual clearance (CL). From the individual primary parameters, the area under the curve (AUC), half-life (t1/2), and central elimination rate constant (K10) were estimated. We performed a repeated-measures analysis to evaluate whether patient characteristics, disease status, concomitant immunosuppressive therapy, and immunogenicity are associated with IFX Cmin and PK parameters.
We collected 429 Cmin measurements from 112 patients. The median of the Cmin values was 3.62 mg/L (1.47-6.02). Antibodies to IFX (ATI) were detected in 14 patients. The predicted median AUC was 28,421 mg/h/L (22,336-36,903). The median individual predicted CL, K10, and t1/2 values were 4.77 mL/kg/day (3.88-5.90), 0.09 days (0.08-0.12), and 12.22 days (9.49-14.87), respectively. IFX Cmin, AUC, CL, and K10 were significantly influenced by ATI and serum albumin concentrations. Moreover, body weight was significantly associated with AUC, CL, and K10. Patients receiving concurrent immunosuppressive therapy had higher Cmin and AUC values and lower CL and K10 values than those treated with IFX monotherapy. We also observed high intrapatient variability in Cmin values during the study period.
In this repeated-measures study in a population of IBD patients, we observed significant associations between ATI, serum albumin concentration, concomitant immunosuppressive therapy, body weight and gender, and IFX Cmin, and CL. The high PK variability observed in this study supports the need for proactive TDM to optimize the use of IFX as early as possible in IBD patients.
对于已对英夫利昔单抗（IFX）无反应的炎症性肠病（IBD）患者，基于治疗-谷浓度（Trough）的方法进行治疗已被证明是一种具有成本效益的策略。然而，这方面的证据有限，并且对于常规的主动治疗药物监测（TDM）的使用仍存在一些争议。为了支持 IBD 患者 IFX 的常规 TDM 和方案优化，需要更深入地了解影响 IFX 药代动力学（PK）变异性的患者、疾病和治疗相关的因素。本研究旨在使用重复测量设计，确定影响 IBD 患者 IFX PK 和暴露的患者、疾病和治疗相关特征。
我们对 2013 年 7 月至 2017 年 3 月期间接受 IFX 治疗的成年 IBD 患者进行了前瞻性观察性研究。我们获得了重复的 IFX 谷浓度（Cmin）测量值，并实施了之前描述的群体药代动力学模型来估计个体清除率（CL）。从个体的主要参数中，估算了曲线下面积（AUC）、半衰期（t1/2）和中央消除速率常数（K10）。我们进行了重复测量分析，以评估患者特征、疾病状态、伴随免疫抑制治疗和免疫原性是否与 IFX Cmin 和 PK 参数相关。
我们从 112 名患者中收集了 429 次 Cmin 测量值。Cmin 值的中位数为 3.62mg/L（1.47-6.02）。在 14 名患者中检测到了抗 IFX 抗体（ATI）。预测的 AUC 中位数为 28421mg/h/L（22336-36903）。个体预测的 CL、K10 和 t1/2 值中位数分别为 4.77mL/kg/天（3.88-5.90）、0.09 天（0.08-0.12）和 12.22 天（9.49-14.87）。IFX Cmin、AUC、CL 和 K10 均受到 ATI 和血清白蛋白浓度的显著影响。此外，体重与 AUC、CL 和 K10 显著相关。与接受 IFX 单药治疗的患者相比，同时接受免疫抑制治疗的患者的 Cmin 和 AUC 值更高，CL 和 K10 值更低。我们还观察到在研究期间 IFX Cmin 值的个体内变异性较高。
在这项针对 IBD 患者的重复测量研究中，我们观察到 ATI、血清白蛋白浓度、伴随免疫抑制治疗、体重和性别与 IFX Cmin 和 CL 之间存在显著关联。本研究中观察到的高 PK 变异性支持需要积极主动的 TDM，以尽早优化 IBD 患者 IFX 的使用。
