Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis
Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis
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DOI：
10.1002/art.10307
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发表时间：
2002-06-01
影响因子：
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通讯作者：
Furst, DE
中科院分区：
文献类型：
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作者：
Munster, T;Gibbs, JP;Furst, DE
Objective.根据达到Paulus 20%改善标准的患者比例，在接受每日400、800或1，200 mg HCQ的6周负荷方案的类风湿性关节炎（RA）患者中观察到了羟氯喹（HCQ）的剂量-反应关系。本回顾性分析旨在研究血液HCQ和HCQ代谢物浓度与疗效和毒性指标之间的可能关系。此外，我们试图确定是否HCQ/HCQ代谢物水平的进一步调查可能会导致测试这些物质作为一种新的抗风湿药物。活动性RA患者（n = 212）开始为期6周的双盲试验，比较3种不同剂量的HCQ（400、800或1，200 mg/天），随后进行18周的开放标签HCQ治疗（400 mg/天）。反复评价患者的治疗效果和毒性。使用高效液相色谱法对123名患者的血液样本进行HCQ、去乙基羟氯喹（DHCQ）、去乙基氯喹（DCQ）和双去乙基氯喹（BDCQ）水平分析。RA缓解的改良Paulus 20%改善标准的实现被用作主要疗效参数。对申办者报告的不良事件进行分类，并作为毒性结局变量进行分析。采用Logistic回归分析评价疗效和毒性与药物浓度的关系。具有血药浓度数据的患者亚组在所有人口统计学和结局特征方面与较大的研究人群相当。HCQ、DHCQ和DCQ的平均消除半衰期分别为123、161和180小时。Paulus 20%改善标准反应与1-6周血DHCQ浓度之间呈正相关（P < 0.001）。发现眼部不良事件与BDCQ水平之间存在潜在关系（P = 0.036）。Logistic回归分析显示，胃肠道不良事件与第1、2、3周HCQ水平升高相关（P = 0.001-0.021）。血液DHCQ浓度与HCQ治疗效果之间存在微弱但可预测的关系。此外，胃肠道不良事件与血HCQ浓度升高之间存在相关性。这些关系的进一步调查是必要的，看看是否DHCQ可能被引入作为一种新的抗风湿药物。
Objective. A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug.Methods. Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis.Results. The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3.Conclusion. There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.