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

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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.