Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Biodistribution after Intravenous Dosing in Rats

Abstract

Relative biodistribution of FDA-approved innovator and generic sodium ferric gluconate (SFG) drug products was investigated to identify differences in tissue distribution of iron after intravenous dosing to rats. Three equal cohorts of 42 male Sprague-Dawley rats were created with each cohort receiving one of three treatments: (1) the innovator SFG product dosed intravenously at a concentration of 40 mg/kg; (2) the generic SFG product dosed intravenously at a concentration of 40 mg/kg; (3) saline dosed intravenously at equivalent volume to SFG products. Sampling time points were 15 min, 1 h, 8 h, 1 week, two weeks, four weeks, and six weeks post-treatment. Six rats from each group were sacrificed at each time point. Serum, femoral bone marrow, lungs, brain, heart, kidneys, liver, and spleen were harvested and evaluated for total iron concentration by ICP-MS. The ICP-MS analytical method was validated with linearity, range, accuracy, and precision. Results were determined for mean iron concentrations (µg/g) and mean total iron (whole tissue) content (µg/tissue) for each tissue of all groups at each time point. A percent of total distribution to each tissue was calculated for both products. At any given time point, the overall percent iron concentration distribution did not vary between the two SFG drugs by more than 7% in any tissue. Overall, this study demonstrated similar tissue biodistribution for the two SFG products in the examined tissues.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: In Vitro Cellular Uptake

“…In the same year, the European Medicines Agency (EMA) published a reflection paper on the non-binding data requirements of follow-on nanoparticle iron medicinal product applications, recommending the studies requested by the FDA with additional non-clinical studies (e.g., characterization of RES uptake, biodistribution in animal models) [ 33 ]. Coupled with the iron biodistribution study in rats [ 40 ], the current in vitro cellular uptake studies have confirmed that the FDA’s currently recommended bioequivalence studies for SFG complex drug products are sufficiently sensitive to capture potential differences between brand and generic formulations in the absence of other non-clinical studies recommended by the EMA.…”

“…In addition to a biodistribution study in rats [ 40 ], we conducted in vitro cellular uptake studies to compare the iron uptake of the brand IV iron drug and its generic version in MPS. Macrophages are among the first players responding to nanoparticle exposure.…”

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Physicochemical Characterization

“…In addition, FDA-initiated research will evaluate brand-to-generic equivalence, especially the labile iron level, of parenteral SFG complex products in human subjects. The follow-up cellular uptake [ 16 ] and biodistribution [ 17 ] studies were conducted to confirm that the differences observed in some of the physicochemical tests between Ferrlecit and generic SFG do not impact the in vivo biological activities.…”

“…The objective of the current study was to conduct physicochemical characterizations between Ferrlecit and its generic counterpart using state-of-the-art analytical technologies in support of follow-up in vitro cellular uptake [ 16 ] and rat biodistribution [ 17 ] studies. In this report, we present inductively coupled plasma-mass spectrometry (ICP-MS), total organic carbon (TOC) measurement, thermogravimetric analysis (TGA), viscosity measurement, cryo-TEM, AFM, SV-AUC, GPC and AFFF methods for the physicochemical characterizations of the innovator and generic SFG complex products.…”

Determination of Non-Transferrin Bound Iron, Transferrin Bound Iron, Drug Bound Iron and Total Iron in Serum in a Rats after IV Administration of Sodium Ferric Gluconate Complex by Simple Ultrafiltration Inductively Coupled Plasma Mass Spectrometric Detection

“…The drug had clearance of 0.31 mL/min/kg and volume of distribution of 0.05 L/kg. The drug also demonstrated transient elevations is NTBI and was used for determination of intravenous sodium ferric gluconate complex in a biodistribution study [ 22 ].…”