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.
This proposal is designed to compare and define in vitro methods of measuring labile iron release with the use of intravenous iron complex formulations that can predict formation of non-transferrin bound iron in vivo. The results of this study will improve equivalence standards for approval of generic IV iron complex formulations.