Evaluation of Iron Species in Healthy Subjects Treated with Generic and Reference Sodium Ferric Gluconate

项目摘要：贫血是慢性肾脏疾病患者的并发症 (CKD)。静脉注射铁胶体制剂(氢氧化铁核心络合物 碳水化合物壳)是目前FDA批准的治疗方案。一个认可的熨斗 制剂是葡萄糖酸铁钠，以Ferrlecit®品牌生产。 名为Nulecit®的仿制药于2011年3月获得FDA批准。很快就会 此后，欧洲药品管理局发表了一篇论文，提出 普通铁制剂，包括葡萄糖酸铁，会增加体内的不稳定水平 铁[也称为非转铁蛋白结合铁(NTBI)]会导致中毒。因此，临床上 比较静脉注射非专利药和品牌药体内“活性铁”水平的研究 人们迫切需要铁的配方。这项研究的目标是进行一项 前瞻性、随机、双向交叉研究，比较血浆、总铁(TI)、 转铁蛋白结合铁(TBI)和非转铁蛋白结合铁(NTBI)(或“不稳定铁”) 接受Ferrlecit®(参考)或Nulecit®(非专利)治疗的健康受试者 注射以确定“活性铁”浓度是否存在差异。 两种配方。每种复合体处理对氧化水平的影响 将测量压力和毒性。具体目标如下：(一) 将对市场品牌(RLD)和通用葡萄糖酸铁钠产品进行表征 关于效力、杂质和其他药品质量属性；(2)严格 确定血浆TI、TBI和NTBI浓度的生物分析方法将是 已开发；(3)比较血浆的前瞻性、随机、双向交叉研究 对服用仿制药和RLD的健康受试者进行TI、TBI、NTBI水平测定； (4)非专利和RLD引起的氧化应激和毒性将用In 体外和体内生物标志物；(5)研究期间的副作用或不良反应 将监测期间；(6)统计分析，以确定是否有 在NTBI水平和其他方面，普通和RLD之间的显著差异将是 已执行。在这些研究结束时，私人投资顾问将会收集比较 关于参照物的物理化学和结构性质的体外数据和 非专利葡萄糖酸铁产品。量化体内游离水平的临床数据 铁、氧化应激生物标志物和毒性 还将获得所提供的葡萄糖酸铁产品的类型的功能。

Project Summary: Anemia is a complication in patients with Chronic Kidney Disease (CKD). IV injection of iron colloid preparations (iron-hydroxide core complexes in carbohydrate shells) is a current FDA approved treatment regimen. One approved iron preparation is sodium ferric gluconate, manufactured under the brand name Ferrlecit®. A generic version named Nulecit® was FDA approved in March 2011. Shortly thereafter, the European Medicines Agency published a paper that proposed that generic iron preparations, including ferric gluconate, deliver increased levels of `labile iron' [also known as non-transferrin bound iron (NTBI)] leading to toxicity. Thus, clinical studies to compare in vivo levels of `labile iron' from IV delivered generic versus brand iron-formulations are urgently needed. The goal of this study is to perform a prospective, randomized, 2-way crossover study to compare plasma, total iron (TI), transferrin bound iron (TBI), and non-transferrin bound iron (NTBI) (or `labile iron') in healthy subjects treated with either Ferrlecit® (reference) or Nulecit® (generic) injections to determine if there are differences in `labile iron' concentrations between the two formulations. The effects of treatment with each complex on levels of oxidative stress and toxicity will be measured. The following specific aims will be pursued: (1) Market brand (RLD) and generic sodium ferric gluconate products will be characterized with respect to potency, impurity, and other drug product quality attributes; (2) Rigorous bio-analytical methods to determine plasma TI, TBI, and NTBI concentrations will be developed; (3) A prospective, randomized, 2-way crossover study to compare plasma TI, TBI, NTBI levels in healthy subjects treated with generic and RLD will be carried out; (4) Oxidative stress and toxicity caused by generic and RLD will be measured with in vitro and in vivo biomarkers; (5) Side effects or adverse reactions during the study period will be monitored; (6) Statistical analysis to determine whether there are any significant differences between generic and RLD in NTBI levels and others will be performed. At the conclusion of these studies, the PIs will have collected comparative in vitro data regarding the physiochemical and structural properties of the reference and generic ferric gluconate products. Clinical data that quantifies in vivo levels of free (labile or non-transferrin bound) iron, oxidative stress biomarkers and toxicity, as a function of the type of iron gluconate product delivered will also have been obtained.