Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia.
Monash University, Melbourne, VIC, Australia.
Aliment Pharmacol Ther. 2020 Mar;51(6):612-628. doi: 10.1111/apt.15643. Epub 2020 Jan 21.
Clinical application of therapeutic drug monitoring (TDM) to optimise anti-TNF therapies in patients with IBD depends upon target ranges.
To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab.
A systematic review was performed, and relevant literature was summarised and critically examined.
Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area-under-receiver-operator-curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end-points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8-5.7 µg/mL are reported depending upon end-points used, with consistent AUROC 0.68-0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9-11.8 µg/mL (AUROC 0.66-0.83) in some studies, but no cut-off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design.
Evidence for exposure-response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.
治疗药物监测（TDM）在优化 IBD 患者的抗 TNF 治疗中的临床应用取决于目标范围。
回顾确定治疗范围的方法，并批判性地比较和对比其在英夫利昔单抗和阿达木单抗中的应用。
进行了系统评价，并对相关文献进行了总结和批判性检查。
治疗范围的上限由毒性、平台反应和成本决定。下限由体外和/或体内最佳作用靶点浓度、药物水平与临床疗效的相关性（使用 AUROC 分析）决定。在 43 项研究中，英夫利昔单抗和阿达木单抗水平测量的时间、终点（临床缓解至黏膜愈合）、临床环境（活动期疾病与维持期）以及 TDM 的原因（主动与被动）存在巨大差异。在英夫利昔单抗的维持期，根据所使用的终点，报告了较低的谷浓度 2.8-5.7µg/mL，具有一致的 AUROC 0.68-0.77。阿达木单抗 TDM 目标甚至更加不一致，一些研究中下限为 5.9-11.8µg/mL（AUROC 0.66-0.83），而在其他研究中，没有可以确定的截止值与结果显著相关，这与固有药代动力学和药效学差异以及研究设计的异质性有关。
英夫利昔单抗比阿达木单抗的暴露-反应关系证据更强。由于药物水平测量的环境存在异质性，治疗范围也有所不同。在解释证据并将其扩展到 IBD 患者的治疗策略时，需要考虑这些因素。
