Development of an Algorithm Incorporating Pharmacokinetics of Adalimumab in Inflammatory Bowel Diseases
Development of an Algorithm Incorporating Pharmacokinetics of Adalimumab in Inflammatory Bowel Diseases
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DOI：
10.1038/ajg.2014.146
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发表时间：
2014-08-01
影响因子：
9.8
通讯作者：
Paul, S.
中科院分区：
文献类型：
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作者：
Roblin, Xavier;Rinaudo, M.;Paul, S.
目的：提出了几种基于英夫利昔单抗（IFX）谷水平和IFX抗体测量的决策算法。这些算法是否可以外推到阿达木单抗（ADA）的药代动力学尚未确定。方法：一项前瞻性研究纳入了所有连续的炎症性肠病（IBD）患者，这些患者在每2周服用40mg ADA时出现疾病发作。所有患者对ADA治疗均有初步反应，且抗肿瘤坏死因子（TNF）初始化。对ADA谷水平和抗ADA抗体（AAA）进行盲法测定（Elisa LISA-Tracker, Theradiag）。所有患者均以ADA每周40mg为优化剂量。4个月后，在没有临床缓解（CR；克罗恩病活动性指数< 150克罗恩病（CD），梅奥评分< 2溃疡性结肠炎）的情况下，患者接受IFX治疗。根据ADA谷底水平和既往研究将患者分为三组：A组，ADA > 4.9 μ g/ml；B组ADA < 4.9 μ g/ml，未检出AAA (< 10 ng/ml)；C组ADA < 4.9 μ g/ml， AAA组> 10 ng/ml。结果：共纳入82例患者（55%为CD，平均年龄43岁，病程7.4年，ADA治疗持续时间17个月）。优化ADA治疗后，A组患者达到CR的比例为29.2% (N = 41)， B组为67% （N = 24)， C组为12% (N = 17)， A/B组与B/C组间P < 0.01）。复发时的c反应蛋白水平、病程、ADA治疗持续时间和IBD类型不能预测ADA优化后的CR。B组对ADA优化的反应（15个月）明显比A组和C组（分别为4和5个月）更持久。在ADA优化失败的患者中，有52例（63%）接受了IFX治疗，其中30.6%的患者达到了CR，在A、B和C组中，IFX启动后的CR率分别为6.9%、25%和80% （C/A组和C/B组之间P < 0.01）。C组患者对IFX的反应时间明显高于A、B组（14个月vs. 3个月和5个月，P < 0.01）。结论：在67%的ADA优化后病例中，无AAA的低ADA谷底水平是临床反应的强烈预测因素。相反，低ADA水平且可检测到AAA与ADA失败相关，应考虑改用IFX。在90%的病例中，ADA过水平> - 4.9 μ g/ml与两种抗tnf药物（ADA和IFX）失效相关，应考虑改用其他药物。
OBJECTIVES: Several decision algorithms based on the measurement of infliximab (IFX) trough levels and antibodies to IFX have been proposed. Whether such algorithms can be extrapolated to the pharmacokinetics of adalimumab (ADA) has yet to be determined.METHODS: A prospective study included all consecutive patients with inflammatory bowel disease (IBD) having a disease flare while being on ADA 40 mg every 2 weeks were included. All patients were primary responders to ADA therapy and were anti-tumor necrosis factor (TNF) naive. ADA trough levels and antibodies against ADA (AAA) were measured blinded to clinical data (Elisa LISA-Tracker, Theradiag). All patients were optimized with ADA 40 mg weekly. Four months later, in the absence of clinical remission (CR; Crohn's disease activity index < 150 for Crohn's disease (CD), and Mayo score < 2 for ulcerative colitis), patients were treated with IFX therapy. Patients were divided into three groups based on ADA trough levels and based on previous studies: group A, ADA > 4.9 mu g/ml; group B, ADA < 4.9 mu g/ml and undetectable levels of AAA (< 10 ng/ml); and group C, ADA < 4.9 mu g/ml and AAA > 10 ng/ml.RESULTS: A total of 82 patients were included (55 % CD; mean age = 43 years, disease duration = 7.4 years, duration of ADA therapy = 17 months). After optimization of ADA treatment, 29.2 % of patients achieved CR in group A (N = 41), 67 % in group B (N = 24), and 12 % in group C (N = 17; P < 0.01 between groups A/B and B/C). C-reactive protein level at the time of relapse, disease duration, duration of ADA therapy, and IBD type was not predictive of CR after ADA optimization by univariate analysis. The response to ADA optimization was significantly more durable in group B (15 months) than in groups A and C (4 and 5 months, respectively). Fifty-two patients who failed following ADA optimization (63 %) were treated with IFX, and 30.6 % of them achieved CR. CR rates following IFX initiation were 6.9 %, 25 %, and 80 % in groups A, B, and C, respectively (P < 0.01 between groups C/A and between groups C/B). Duration of response to IFX was significantly higher in group C than in groups A and B (14 vs. 3 and 5 months, respectively, P < 0.01).CONCLUSIONS: The presence of low ADA trough levels without AAA is strongly predictive of clinical response in 67 % of cases after ADA optimization. Conversely, low ADA levels with detectable AAA are associated with ADA failure, and switching to IFX should be considered. ADA trough levels > 4.9 mu g/ml are associated with failure of two anti-TNF agents (ADA and IFX) in 90 % of cases, and switching to another drug class should be considered.