Median effect analysis of efficacy versus adverse effects of immunosuppressants
Median effect analysis of efficacy versus adverse effects of immunosuppressants
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DOI：
10.1067/mcp.2001.116309
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发表时间：
2001-07-01
影响因子：
6.7
通讯作者：
Kramer, WG
中科院分区：
文献类型：
--
作者：
Kahan, BD;Kramer, WG
背景：采用描述浓度-效应关系的严格模型（中位效应分析）来定量人肾移植中的免疫抑制与不良反应。方法：中位效应方程用于分析从三项临床研究中收集的数据，包括两项 III 期盲法安慰剂对照试验（n = 1295 名患者），比较西罗莫司与硫唑嘌呤或安慰剂治疗添加到环孢素（INN，环孢素）/泼尼松方案中的情况以及西罗莫司/硫唑嘌呤/泼尼松（不存在环孢素）II 期队列（n = 41 名患者）。 结果：临床效果与药物浓度相关，如中值效应方程所示。单独使用西罗莫司或环孢菌素可使药物浓度分别降低 5 倍和 2.2 倍，使 90% 的患者无排斥反应，这表明两种药物之间存在协同相互作用。此外，使 50% 患者无排斥反应的西罗莫司浓度比导致 50% 患者出现血小板减少症或高甘油三酯血症的浓度分别低约 200 倍和 60 倍。西罗莫司高胆固醇血症发生的中位效应分析的相关系数比环孢菌素更稳健。尽管 50% 的无排斥反应患者与 50% 的受高胆固醇血症影响的患者的浓度相似，但 90% 的患者无排斥反应的浓度与受高胆固醇血症影响的患者的浓度之间存在 7 倍的差异。结论：中位效应分析提供了一个有用的工具，用于评估药物相互作用以及免疫抑制剂的治疗作用与毒性作用之间的窗口。目前的分析表明西罗莫司和环孢菌素之间存在协同相互作用。
Background: A rigorous model to describe concentration-effect relations-the median effect analysis-was applied to quantitate immunosuppressive versus adverse effects in human renal transplantation.Methods: The median effect equation was used to analyze data collected from three clinical studies, including the two phase III blinded, placebo-controlled trials (n = 1295 patients) of sirolimus versus azathioprine or placebo treatment added to a cyclosporine (INN, ciclosporin)/prednisone regimen and a sirolimus/azathioprine/prednisone (in the absence of cyclosporine) phase II cohort (n = 41 patients).Results: The clinical effects correlated with drug concentrations as expressed by the median effect equation. Sirolimus or cyclosporine alone permitted drug concentrations that were 5-fold and 2.2-fold lower, respectively, to render 90% of patients rejection-free, suggesting a synergistic interaction between the two drugs. Further, the sirolimus concentrations to render 50% of patients rejection-free were about 200-fold and 60-fold less, respectively, than the concentration that caused 50% of patients to experience thrombocytopenia or hypertriglyceridemia. The correlation coefficient of the median effect analysis for the occurrence of hypercholesterolemia was more robust for sirolimus than for cyclosporine. Although the concentrations for 50% of patients rendered rejection-free versus 50% affected by hypercholesterolemia were similar, a 7-fold difference was calculated between the concentrations at which 90% of patients were free of rejection versus patients who were affected by hypercholesterolemia.Conclusion: The median effect analysis proffers a useful tool to assess both drug interactions and the windows between therapeutic versus toxic effects of immunosuppressive agents. The current analysis suggests a synergistic interaction between sirolimus and cyclosporine.