Performance of Redox Active and Chelatable Iron Assays to Determine Labile Iron Release From Intravenous Iron Formulations.

Emerging data from global markets outside the United States, where many generic iron sucrose formulations are available, have revealed that non-US generic intravenous (i.v.) iron formulations may have iron release profiles that differ from the reference listed drug (RLD). The first generic i.v. iron approved in the United States was sodium ferric gluconate complex in 2011. We evaluated chelatable and redox labile iron assay methods to measure the amount of labile iron released from i.v. iron formulations in biorelevant matrices in vitro. The majority of published labile iron assays evaluated were not suitable for use in vitro due to overwhelming interference by the presence of the i.v. iron products. However, an optimized high-performance liquid chromatography (HPLC)-based method performed well for use in vitro labile iron detection in a biorelevant matrix. Application of this method may enhance bioequivalence evaluation of generic i.v. iron formulations in the future.

Plasma pharmacokinetics of two consecutive doses of ferumoxytol in healthy subjects.

Intravenous (IV) iron is used to treat iron-deficiency anemia in patients with chronic kidney disease (CKD). Ferumoxytol is a novel iron formulation administered rapidly as two IV boluses of 510 mg each. In this placebo-controlled, double-blind, parallel-group study, 58 healthy volunteers received ferumoxytol in two 510 mg doses administered 24 h apart. Population pharmacokinetics (PK) analysis was conducted, and a two-compartment open model with zero-order input and Michaelis-Menten elimination was found to best describe the data. The population mean estimates for volume of distribution of the central compartment (V(1)), maximal elimination rate (V(max)), and ferumoxytol concentration at which rate of metabolism would be one-half of V(max) (K(m)) were 2.71 l, 14.3 mg/h, and 77.5 mg/l, respectively. When the effect of body weight on V(1) was added in the analysis, interindividual variability was found to be reduced. A noncompartmental analysis of two simulated 510-mg ferumoxytol doses was also performed to provide clinically interpretable data on half life and exposure. Ferumoxytol given as two consecutive 510-mg doses was well tolerated.

The role of sevelamer in achieving the kidney disease outcomes quality initiative (K/DOQI) guidelines for hyperphosphatemia.

BACKGROUND: End-stage renal disease (ESRD) is a chronic health care problem associated with multiple co-morbidities and escalating costs. Disregulation of mineral metabolism (principally hyperphosphatemia and hypercalcemia) contributes to substantial morbidity and mortality. Accordingly, new and more-aggressive Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines from the National Kidney Foundation promote lower serum phosphorus (3.5-5.5 mg/dL), lower calcium (8.4-9.5 mg/dL), and lower calcium-phosphorus product (< 55 mg(2)/dL(2)) targets. REVIEW FINDINGS: Traditional calcium-based and metal-based phosphate binders are effective but are associated with side effects and toxicity that limit their use. Achieving rigorous K/DOQI goals demands higher therapeutic doses of phosphate binders and may require more-aggressive use of calcium-free and metal-free phosphate binders. Sevelamer hydrochloride is a calcium- and metal-free polymer that binds phosphate effectively without contributing to calcium load or metal accumulation. In the Treat-to-Goal trial, sevelamer-treated dialysis patients had less progression of coronary and aortic calcification than patients treated with calcium-based binders. This offers the potential promise of reducing cardiovascular morbidity and mortality. The 800-mg tablet (Renagel) increases the daily sevelamer dose while reducing the number of tablets required per meal. Nine of the 800-mg tablets per day (3 x 800-mg tablets tid with meals) of sevelamer monotherapy have been shown to achieve K/DOQI serum phosphorus and calcium-phosphorus product targets. CONCLUSION: In summary, this review of the current evidence-base concludes that the new, more-aggressive, K/DOQI goals limit the use of metal-based and calcium-based phosphate binders. Sevelamer offers the advantages of lowering serum phosphorus without the risks of calcium or metal accumulation - and offers the promise of slowing the progression of vascular calcification and potentially reducing the morbidity and mortality of hemodialysis patients.