The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis - Results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial
The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis - Results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial
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DOI：
10.1002/art.10302
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发表时间：
2002-06-01
影响因子：
--
通讯作者：
Keystone, EC
中科院分区：
文献类型：
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作者：
Clair, EWS;Wagner, CL;Keystone, EC
Objective.研究抗肿瘤坏死因子A单克隆抗体英夫利西单抗（infliximab）血清浓度与类风湿关节炎（RA）患者临床疗效的关系。从428例活动性RA受试者中采集多份血样，这些受试者入组了一项多中心、随机、双盲、安慰剂对照试验（ATTRACT [伴随治疗的风湿性关节炎抗肿瘤坏死因子试验]），评价英夫利西单抗治疗的临床疗效和安全性。采用酶联免疫吸附试验测定血清英夫利西单抗水平。使用广义逻辑回归技术分析剂量反应趋势。药代动力学模型用于预测模拟输注后英夫利西单抗的血清浓度，剂量和给药间隔在试验中未评估。在第54周，每8周接受3 mg/kg英夫利西单抗治疗的受试者中有26%的受试者血清中英夫利西单抗谷浓度不可检测，这一比例显著高于其他3个治疗组（P < 0.001）。美国流变学学会（ACR）响应幅度增加（通过ACR-N测量，一种根据ACR 20%缓解标准得出的临床改善的连续指标）和血清C-反应蛋白水平较基线降低幅度较大均与英夫利西单抗血清谷浓度较高相关（P < 0.001），放射学关节损伤进展较少（P = 0.004），为剂量-反应关系提供了支持。药代动力学模型预测，与增加100 mg剂量相比，将给药间隔从8周缩短至6周将产生更高的血清谷浓度。这些结果表明，一些RA患者可能受益于英夫利西单抗给予高于3 mg/kg的剂量或频率高于每8周一次。
Objective. To investigate the relationship between serum concentrations of infliximab, a monoclonal antitumor necrosis factor a antibody, and clinical improvement from infliximab therapy for rheumatoid arthritis (RA).Methods. Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the clinical efficacy and safety of infliximab therapy. Serum levels of infliximab were measured by enzyme-linked immunosorbent assay. Dose-response trends were analyzed using generalized logistic regression techniques. Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial.Results. At week 54, 26% of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (P < 0.001). Increased magnitude of American College of Rheumatology (ACR) response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR 20% response criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (P < 0.001), as was less progression of radiographic joint damage (P = 0.004), providing support for a dose-response relationship. Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg.Conclusion. These results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.