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

贫血是慢性肾脏病患者的一种并发症 （CKD）。IV注射铁胶体制剂（铁-氢氧化物核心络合物， 碳水化合物壳）是目前FDA批准的治疗方案。一个批准的熨斗 该制剂是葡萄糖酸铁钠，以商品名Ferrlecit®制造。 名为Nulecit®的通用版本于2011年3月获得FDA批准。不久 此后，欧洲药品管理局发表了一篇论文，提出， 一般的铁制剂，包括葡萄糖酸铁， 铁[也称为非转铁蛋白结合铁（NTBI）]导致毒性。因此，临床 比较静脉注射非专利药与品牌药的体内“不稳定铁”水平的研究 迫切需要铁制剂。本研究的目的是进行一项 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®（参比品）或Nulecit®（仿制品）治疗的健康受试者 注射，以确定是否有“不稳定铁”浓度之间的差异， 两种配方。每种复合物处理对氧化水平的影响 将测量压力和毒性。具体目标如下：（1） 将对市场品牌（RLD）和通用葡萄糖酸铁钠产品进行表征 关于效价、杂质和其他制剂质量属性;（2）严格 将采用生物分析方法测定血浆TI、TBI和NTBI浓度， （3）一项前瞻性、随机、双向交叉研究，比较血浆 将在接受仿制药和RLD治疗的健康受试者中进行TI、TBI、NTBI水平; (4)仿制药和RLD引起的氧化应激和毒性将在 体外和体内生物标志物;（5）研究期间的副作用或不良反应 （6）统计分析，以确定是否有任何 在NTBI水平和其他方面，仿制药和RLD之间存在显着差异， 执行。在这些研究结束时，PI将在以下方面收集比较数据： 关于参比品理化和结构特性的体外数据， 通用葡萄糖酸铁产品。临床数据，定量体内游离 （不稳定或非转铁蛋白结合）铁，氧化应激生物标志物和毒性，作为 也将获得所递送的葡萄糖酸铁产品类型的功能。

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.