SP394PHARMCOKINETICS OF TRIFERIC ADMINISTERED IV TO HEALTHY VOLUNTEERS: NO EFFECT ON HEPCIDIN OR OXIDATIVE STRESS MARKERS

Abstract

Introduction and Aims: Triferic™is a complex iron salt under investigation for administration via hemodialysate. Triferic crosses the dialyzer membrane and binds to apotransferrin during hemodialysis. Triferic is designed to replace the obligatory iron losses due to uremic GI bleeding, phlebotomy and retained blood in the dialyzer circuit in HD patients. Triferic administered via dialysate rapidly transfers across the dialyzer membrane resulting in an increase in serum iron (sFe) and transferrin saturation (TSAT) at the end of dialysis. Serum iron and TSAT values return to the baseline by the start of the next dialysis session. The current study examined the pharmacokinetics of intravenously administered Triferic to assess the amount of iron administered from dialysate in the Triferic clinical studies. Methods:We conducted a double-blind, placebo controlled single ascending dose study in 48 subjects in 6 cohorts of healthy iron-replete volunteers (25 Male, 33 Female; age range 19-55 years). Six (6) patients received intravenous (IV) Triferic and 2 received placebo in each cohort. Two infusion times were chosen to reflect the average time on dialysis for CKD-HD patients (4 hr) as well as to establish a safe maximum dose level (12 hr). Single doses of 2.5, 5.0, 7.5 and 10.0 mg of Triferic iron were administered intravenously over 4 hours and doses of 15 and 20 mg Triferic iron were administered over 12 hours. Volunteers were admitted to the CRC the day before test drug administration and remained for 48 hours after the infusion ceased. Serum samples were analyzed for total iron (sFetot) and transferrin bound iron (TBI) via a novel validated assay. Serum hepcidin-25, isoprostanes, isofurans, malondialdehyde and IL-6 were measured using existing validated assays. Results: A marked diurnal variation in sFetot was present in placebo patients. Total Fe and TBI increased rapidly during the 4 and 12 hour infusions with Tmax equal to the end of infusion. Baseline corrected Cmax and AUC0-α increased proportional to the dose up to a TSAT of 100%. SFe-total and TBI were similar in concentration. Triferic iron was rapidly cleared with an apparent t1/2 of approximately 2 hours. There was a high inter-individual range of hepcidin -25 concentrations. At the end of infusion, no change from baseline in hepcidin -25 was observed at doses of 2.5 to 10 mg over 4 hours. At doses of 15 and 20 mg administered over 12 hours, there was an increase in hepcidin-25 of 6.1 ± 4.4 nM (p=NS) from baseline. However, all hepcidin-25 values remained within the reference range for age and sex. Markers of oxidative stress and inflammation were also not affected by increasing doses of Triferic. No dose related adverse events were observed. Conclusions:We conclude that parenteral Triferic iron is rapidly bound to transferrin and cleared from the circulation without increasing hepcidin, inflammation or oxidative stress. Triferic had a favorable safety profile compared to placebo. (Figure Presented).