Mattioli Francesca, Puntoni Matteo, Marini Valeria, Fucile Carmen, Milano Giulia, Robbiano Luigi, Perrotta Silverio, Pinto Valeria, Martelli Antonietta, Forni Gian Luca
Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Genoa, Italy.
Eur J Haematol. 2015 Apr;94(4):310-7. doi: 10.1111/ejh.12419. Epub 2014 Sep 17.
Bioavailability of deferasirox (DFX) is significantly affected by the timing of administration relative to times and to composition of meals. Its elimination half-life is also highly variable - in some patients as a result of gene polymorphisms. Understanding whether deferasirox plasma levels are related to specific characteristics of patients could help physicians to devise a drug regimen tailored the individual patient.
We analyzed deferasirox plasma concentrations (CDFX ) in 80 patients with transfusion-dependent anemias, such as thalassemia, by a high performance liquid chromatography (HPLC) assay. We used a multivariate linear regression model to find significant associations between CDFX and clinical/demographical characteristics of patients. All patients were genotyped for UGT1A1.
Fifty-six patients were female, 24 were male, the great majority (88%) affected by β-thalassemia, and 15 were children and adolescents. No statistical correlation was detectable between CDFX and DFX dose (P = 0.6). Age, time from last drug intake to blood sampling, and ferritin levels in the 6 months before study initiation were significantly and inversely associated with CDFX in univariate analysis. In the multivariate analysis, the only two factors independently and inversely associated with CDFX levels were time from last drug intake to blood sampling and ferritin levels (P = 0.006). A significant inverse correlation (P = 0.03) was observed between CDFX and UGT1A1*28 gene polymorphism, but only in patients with levels of lean body mass (LBM) below the median (P for interaction = 0.05).
The results could indicate that a higher plasma DFX concentration could be associated with greater chelation efficacy. As a correlation between dose and CDFX was not demonstrated, it seems useful to monitor the concentrations to optimize and determine the most appropriate dose for each patient. Interesting results emerged from the analysis of genetic and physical characteristics of patients: LBM was a borderline significant effect modifier of the relationship between UGT1A1 polymorphisms and CDFX . Individual patient-tailored dosing of DFX should help to improve iron chelation efficacy and to reduce dose-dependent drug toxicity.
与进餐时间和膳食组成相比，去铁胺（DFX）的生物利用度受给药时间的显著影响。其消除半衰期也高度可变——在一些患者中是由于基因多态性。了解去铁胺血浆水平是否与患者的特定特征相关，有助于医生为个体患者制定量身定制的药物治疗方案。
我们通过高效液相色谱（HPLC）测定法分析了80例依赖输血的贫血患者（如地中海贫血患者）的去铁胺血浆浓度（CDFX）。我们使用多元线性回归模型来发现CDFX与患者临床/人口统计学特征之间的显著关联。所有患者均进行了UGT1A1基因分型。
56例为女性，24例为男性，绝大多数（88%）患有β地中海贫血，15例为儿童和青少年。CDFX与DFX剂量之间未检测到统计学相关性（P = 0.6）。在单变量分析中，年龄、从上次服药到采血的时间以及研究开始前6个月的铁蛋白水平与CDFX显著负相关。在多变量分析中，与CDFX水平独立且负相关的仅有的两个因素是从上次服药到采血的时间和铁蛋白水平（P = 0.006）。在CDFX与UGT1A1*28基因多态性之间观察到显著的负相关（P = 0.03），但仅在瘦体重（LBM）水平低于中位数的患者中存在（交互作用P = 0.05）。
结果可能表明较高的血浆DFX浓度可能与更强的螯合疗效相关。由于未证明剂量与CDFX之间的相关性，监测浓度以优化并确定每位患者的最合适剂量似乎是有用的。对患者的遗传和身体特征分析得出了有趣的结果：LBM是UGT1A1多态性与CDFX之间关系的临界显著效应修饰因子。为个体患者量身定制DFX给药应有助于提高铁螯合疗效并降低剂量依赖性药物毒性。
