2001
   Basel, Switzerland

Iron kinetics: when drug loss by sampling is critical in data analysis

Kimko, Hui C.

Center for Drug Development Science, Georgetown University Medical Center, Washington, DC, USA

Transferrin bound iron (TBI) is the form in which iron is used by the bone marrow for erythropoiesis. Rapid delivery of iron to transferrin and, consequently, to the bone marrow has been postulated. Studies on iron dextran using sequential bone marrow biopsy showed that, by 7 days, only 50% of the injected iron was delivered to the bone marrow with the residual amount available over 3 months. Healthy iron-deficient volunteers were enrolled in a cross-over study of a new IV iron complex, Drug X, in which 14 subjects were randomized to high and low doses. Blood was sampled for 72 hours at 30 pre-defined intervals for total serum iron and TBI. Total serum iron and TBI concentrations were simultaneously fitted by nonlinear mixed effects modeling. The iron loss from sampling was considered. The final model fit the observed time-courses of drug-bound iron and TBI well. Drug-bound iron was cleared rapidly, suggesting initial reticulo-endothelial system (RES) uptake. Under the physiologic assumption that iron delivery to transferrin follows saturation kinetics, delivery was estimated to reach a maximum rate (Vmax) of 5 - 11 mg/h, which is consistent with the result from the others. The concentration to reach half of Vmax was 15 ug/ml. These data indicate that almost 90% of the iron in Drug X is available for erythropoiesis within 24 hours in iron deficient subjects.