Plasma Pharmacokinetics of Two Consecutive Doses of Ferumoxytol in Healthy Subjects

Abstract

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.

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

“…In plasma, the elimination half-life of FMX was 22.1 hours (n ¼ 14; 95% CI, 19.7-24.5; Fig. 3C), consistent with previously published data in healthy subjects (36,37) and comparable with the reported half-life of nal-IRI (11,35). Plasma exposure (AUC 0!t ) for FMX and nal-IRI were correlated (r ¼ 0.7528; P ¼ 0.0030).…”

Evaluating Plasma Pharmacokinetics of Intravenous Iron Formulations: Judging Books by Their Covers?

“…This is arguably one of the larger PK analyses of IV iron plasma data to date, and ferumoxytol offers the distinct advantage of being able to be directly measured by nuclear magnetic resonance. The authors show that, as previously published, ferumoxytol plasma concentration-time profiles were best fitted with a two-compartment model with nonlinear elimination, consistent with the known capacity-limited metabolism by the reticuloendothelial system [3].…”

“…59 Fe) to distinguish the IV iron formulation from endogenous serum iron [2]. It is also not well appreciated by clinicians that IV iron formulations exhibit zero-order or capacity-limited metabolism by the reticuloendothelial system [3]. This results in longer residence time in plasma with higher administered doses, especially with larger molecular weight formulations [3].…”

“…It is also not well appreciated by clinicians that IV iron formulations exhibit zero-order or capacity-limited metabolism by the reticuloendothelial system [3]. This results in longer residence time in plasma with higher administered doses, especially with larger molecular weight formulations [3]. Commercially available IV iron formulations consist of an iron oxyhydroxide core surrounded by carbohydrate shells of various sizes and polysaccharide branch characteristics in colloidal suspensions [4].…”

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

“…58 This results in longer plasma residence times with higher doses, especially with larger molecular weight formulations. 59,60 Thus, doses above the RES capacity will remain circulating until the concentration falls below the capacity limit, at which point the pharmacokinetics become linear or concentration independent. Given their complexity, these agents have not been sufficiently studied with regard to comparative biodistribution, metabolic fate, and potential extracellular and intracellular toxicity.…”