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

预测血清非转铁蛋白结合铁的体外-体内相关模型

基本信息

批准号：
8665279
负责人：
Amy Barton Pai
金额：
$ 50万
依托单位：
ALBANY COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665279
关键词：
vitro vivo correlation model predict

项目摘要

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.

项目摘要静脉（IV）补铁在治疗贫血中具有关键作用。IV铁络合物所有制剂都由被保护性碳水化合物壳包围的氢氧化铁核组成。的铁-碳水化合物复合物被设计成防止不稳定铁从制剂中释放，最终导致体内非转铁蛋白结合铁（NTBI）。NTBI可增强氧化应激，炎症碳水化合物壳的大小和组成预测制剂稳定性和结果。不稳定铁释放。来自非临床研究的数据表明，在欧洲和亚洲，与所列参考品相比，药这些通用化合物分子结构的细微差异似乎有助于研究了一般蔗糖铁产品引起的毒性作用。2011年3月，第一个通用IV铁，葡萄糖酸铁钠复合物（SFGC）被FDA批准。考虑到这些潜在的差异， IV铁复合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）候选仿制药IV铁复合物制剂的模型，将改善当前的FDA等效性这些制剂的标准评价。本申请要实现的具体目标是：体外研究具体目标1。制剂研究-每种待研究的制剂将在以下方面进行充分表征：分子量、粒度分布和物理化学特性。具体目标2。体外不稳定铁的评价-将评价每种IV铁复合物制剂通过检测可螯合铁的试验和测定氧化还原的试验，生理盐水和生物相关血清基质中的活性铁。体内研究具体目标3。临床前种属的药代动力学研究-使用通过测量血清非转铁蛋白结合铁在大鼠模型中进行每种铁络合物制剂。具体目标4。建立体外不稳定铁数据与体内NTBI数据之间的关系- 将采用系统分析方法为每种IV铁络合物制剂建立IVIVC。