An in vitro-in vivo correlation model to predict serum non-transferrin bound iron

项目总结 静脉补铁在贫血的治疗中起着关键作用。四价铁络合物 所有配方都由氢氧化铁核心和保护性碳水化合物外壳组成。这个 铁-碳水化合物复合体旨在防止不稳定的铁从配方中释放出来 最终导致体内的非转铁蛋白结合铁(NTBI)。NTBI可增强氧化应激和 发炎。碳水化合物外壳的大小和组成预测制剂的稳定性和产物 不稳定的铁释放。来自非临床研究的数据表明，通用蔗糖铁配方是可用的 在欧洲和亚洲表现出与所列参考文献不同的物理化学性质 毒品。这些普通化合物的分子结构上的细微差别似乎有助于 研究了普通蔗糖铁产品的毒性效应。2011年3月，第一个通用IV型熨斗， 葡萄糖酸铁钠(SFGC)已获FDA批准。鉴于这些潜在的差异 IV铁复合制剂普通IV铁制剂的安全性需要进一步评估。 本项目的目的是进行严格和系统的体外到体内相关性(IVIVC)。 将改善当前FDA等效性的候选通用IV铁络合物配方的模型 对这些制剂进行标准评价。 此应用程序要实现的具体目标是： 体外研究 具体目标1.配方研究--要研究的每一种配方都将充分说明 分子量、粒度分布和物化特性。 具体目标2.不稳定铁的体外评价--将对每一种静脉注射铁络合物配方进行评价 通过检测可螯合铁的化验和测定氧化还原的化验来检测易失铁的出现 生理盐水和生物悬浮血清基质中的活性铁。 体内研究 具体目标3.临床前物种的药代动力学研究-药物动力学研究 通过测定血清非转铁蛋白结合铁，在大鼠模型中进行每个铁络合物配方的研究。 具体目标4.建立体外活性铁数据和体内NTBI数据之间的关系- 将利用系统分析方法，为每一种静脉注射铁复合体配方建立一个静脉注射用铁化合物。

PROJECT SUMMARY Intravenous (IV) iron supplementation has a pivotal role in treatment of anemia. IV iron complex formulations all consist of a ferric hydroxide core surrounded by a protective carbohydrate shell. The iron-carbohydrate complex is designed to prevent release of labile iron from the formulation that ultimately leads to non-transferrin bound iron (NTBI) in vivo. NTBI can potentiate oxidative stress and inflammation. Size and composition of the carbohydrate shell predicts formulation stability and resultant labile iron release. Data from non-clinical studies indicate that generic iron sucrose formulations available in Europe and Asia exhibit differences in physicochemical properties compared with the reference listed drug. Subtle differences in the molecular structures of these generic compounds appear to contribute to the toxic effects elicited by generic iron sucrose products studied. In March 2011, the first generic IV iron, sodium ferric gluconate complex (SFGC) was approved by the FDA. Given these potential differences in IV iron complex formulations the safety of generic IV iron formulations requires further evaluation. The purpose of this project is to conduct a rigorous and systematic in vitro to in vivo correlation (IVIVC) model for candidate generic IV iron complex formulations that will improve the current FDA equivalence standards evaluation for these formulations. The specific aims to be achieved in this application are: In vitro studies Specific Aim 1. Formulation study -Each formulation to be studied will be fully characterized in terms of molecular weight, particle size distribution and physicochemical characteristics. Specific Aim 2. Evaluation of labile iron in vitro - Each IV iron complex formulation will be evaluated for appearance of labile iron by assays that detect chelatable iron and assays that determine redox active iron in both saline and biorelevant serum matrices. In vivo studies Specific Aim 3. Pharmacokinetic study in preclinical species - Pharmacokinetic studies with the each iron complex formulation conducted in a rat model by measuring serum non-transferrin bound iron. Specific Aim 4. Establish the relationship between in vitro labile iron data and in vivo NTBI data - A systems analysis approach will be utilized to establish an IVIVC for each IV iron complex formulation.