目的:本研究的目的是分析和描述非典型溶血性尿毒综合征(aHUS)和C3肾小球疾病患者的依库珠单抗和补体阻断的浓度,并定义治疗界限,其中有很高的可能性实现治疗功效。
方法:观察性,两性平等,和多中心研究,包括2020年9月至2022年10月在西班牙5家医院诊断为aHUS和C3肾小球病的成人和儿科患者。根据欧洲药品管理局(EMA),Eculizumab以数据表推荐的剂量给药。确定依库珠单抗的给药前后浓度,以及经典补体途径(CH50)的阻断。收集社会人口统计学和临床数据,并计算药代动力学参数。为了建立预测补体阻断的依库珠单抗浓度的临界点,进行受试者工作特征(ROC)曲线分析。最后,根据依库珠单抗浓度,使用Kruskal-Wallis检验对比不同参数的差异.
结果:包括25名患者,19名成人(76.0%)和6名儿科(24.0%),年龄中位数为43.4岁(四分位距(IQR)35.7-48.8)和10.1岁(IQR9.6-11.3),分别。其中,22例(88.0%)患者被诊断为aHUS,3例(12.0%)患者被诊断为C3肾小球病。测定了总共111个依库珠单抗浓度。在维持阶段检测到的平均给药前和给药后浓度值分别为243.8(SD240.6)μg/mL和747.4(标准偏差(SD)444.3)μg/mL,分别。在较高的前剂量浓度下观察到增加的补体阻断(P=.002),并且在较高的前和后剂量浓度下观察到降低的血清肌酐(分别为P=.001和P=.017)。使用ROC曲线,确定剂量前浓度>149.0μg/mL是实现补体阻断的最佳选择,AUC为0.87(0.78-0.95)。最后,观察到高个体间(48.9%变异系数(CV))和低个体间差异(11.9%CV)的依库珠单抗清除率.
结论:本研究报告了aHUS患者中依库珠单抗的超治疗浓度,并定义了比数据表中描述的更高的浓度以实现封锁,从而鼓励依库珠单抗治疗的个性化.
The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy.
Observational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations.
Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) μg/mL and 747.4 (standard deviation (SD) 444.3) μg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (P = .002) and decreased serum creatinine at both higher pre- and post-dose concentrations (P = .001 and P = .017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 μg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed.
The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.