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Published ahead of print on October 17, 2007
Clin J Am Soc Nephrol 2: 1140-1146, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.00830207
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Clinical Pharmacology

Single-Dosage Pharmacokinetics of Sodium Ferric Gluconate Complex in Iron-Deficient Pediatric Hemodialysis Patients

Bradley A. Warady*, Paul A. Seligman{dagger}, and Naomi V. Dahl{ddagger}

* Department of Pediatrics, Section of Pediatric Nephrology, Children's Mercy Hospital, Kansas City, Missouri; {dagger} Department of Medicine, Division of Hematology, University of Colorado School of Medicine, Denver, Colorado; and {ddagger} Watson Laboratories, Morristown, New Jersey

Correspondence: Dr. Bradley A. Warady, Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108. Phone: 816-234-3010; Fax: 816-234-3494; E-mail: bwarady{at}cmh.edu


   Abstract
Top
 Abstract
Introduction
 Concise Methods
 Results
 Discussion
 Disclosures
 References
 
Background and objectives: The clinical use of sodium ferric gluconate complex in iron-deficient pediatric patients receiving hemodialysis was recently approved. This study was designed to describe the pharmacokinetic parameters of the medication.

Design, setting, participants, & measurements: Iron-deficient pediatric (≤15 yr) hemodialysis patients were randomly assigned to two doses (1.5 and 3.0 mg/kg) of sodium ferric gluconate complex. Blood samples taken during a 1-h infusion and at multiple intervals during 48 h were analyzed for total iron, transferrin-bound iron, and sodium ferric gluconate complex–bound iron.

Results: Forty-nine patients (mean age 12.3 ± 2.5 yr) participated in the study. Mean serum iron concentrations rapidly increased in a dosage-dependent manner. A rapid rise in total serum iron was followed by a slower, less prominent rise in transferrin-bound iron. This was qualitatively confirmed by visualization of the transferrin bands from polyacrylamide gel electrophoresis. Single-dose pharmacokinetics of sodium ferric gluconate complex–bound iron was described using noncompartmental analytical methods. Mean values for the 1.5 mg/Kg dose were as follows: t1/2 2.0 ± 0.7 h, Cmax 1287 mcg/dl, Tmax 1.1 ± 0.23 h, Cl 0.69 ± 0.50 L/h, Vd 1.6 ± 0.6 L, AUC0-{infty}. 9499 ± 4089 mcg · hr/dl.

Conclusions: The infusion of sodium ferric gluconate complex to pediatric patients who receive hemodialysis appears to result in a delayed transfer of iron to transferrin, likely after an initial movement through the reticuloendothelial system. Differences noted between the pediatric and adult pharmacokinetic data may result from the unique aspects of the study populations and the respective study designs.


   Introduction
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 Abstract
 Introduction
Concise Methods
 Results
 Discussion
 Disclosures
 References
 
Anemia is a common complication of ESRD owing to a variety of factors (1). Whereas studies have shown anemia to be considerably more prevalent among pediatric dialysis patients than among adult patients, the bulk of the research on anemia in hemodialysis (HD) patients has been conducted in adults. It is widely recognized, however, that pediatric patients who receive HD experience chronic blood loss and resultant iron deficiency (2). In fact, iron loss is expected to be even greater in smaller children than in adults because equal volumes of obligate blood loss with each dialysis session represents a larger fraction of the total iron pool. The Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Recommendations state that "the goals of iron therapy are to avoid storage iron depletion, prevent iron-deficient erythropoiesis, and achieve and maintain target [hemoglobin] levels" (1). For accomplishment of these goals, the preferred route of iron supplementation for children who receive HD is intravenous (1), and sodium ferric gluconate complex (SFGC) was recently approved by the Food and Drug Administration for use in children who receive maintenance HD (3–5).

The pharmacokinetics of SFGC in iron-deficient adults who are not on dialysis was described by Seligman et al. (6). In that study, it was shown that SFGC-derived iron was rapidly transferred to a bioavailable iron compartment as transferrin-bound iron, after digestion in the reticuloendothelial system (RES). No similar information is available for children. As part of the previously mentioned trial of iron repletion therapy with SFGC in iron-deficient pediatric patients who receive HD, the pharmacokinetic properties of SFGC were determined (4).


   Concise Methods
Top
 Abstract
 Introduction
 Concise Methods
Results
 Discussion
 Disclosures
 References
 
This pharmacokinetic evaluation was conducted as part of a prospective, randomized, double-blind, parallel group, multicenter, multiple-dose trial, of intravenous SFGC in pediatric patients who had ESRD and were undergoing long-term HD and recombinant human erythropoietin therapy (4), among all participants who consented to the additional procedure after informed consent. Iron-deficient (transferrin saturation [TSAT] <20% and/or a serum ferritin <100 ng/ml) pediatric patients who had ESRD; were between the ages of 2 and 15 yr, inclusive; and were undergoing long-term HD and receiving concomitant recombinant human erythropoietin therapy were randomly assigned to receive eight doses of either 1.5 or 3.0 mg/kg SFGC. SFGC was diluted in normal saline and infused in a total volume of 25 ml by syringe pump during 1 h, not to exceed 125 mg/dose during each of eight consecutive HD sessions.

The pharmacokinetics of SFGC-bound iron (calculated as total iron minus transferrin-bound iron) was determined immediately after the start of the patient's first SFGC administration. Blood samples (2 ml/sample) for the measurement of total iron and transferrin-bound iron were collected within 5 min before the start of the patient's first SFGC administration and at 30, 60, 75, 90, 120, 180, 240, and 360 min after the start of the first SFGC administration. One additional blood sample was obtained 48 h after the start of the first SFGC infusion (i.e., immediately before the second SFGC infusion). The actual time of all blood collections was documented and used in the calculation of the pharmacokinetic parameters.

For each patient, the total amount of blood collected for the pharmacokinetic analysis was 20 ml (10 samples at 2 ml/sample). Samples were allowed to clot at room temperature (maximum 30 min), and the contents of the tube were centrifuged at approximately 1500 x g for 15 min. The resulting serum samples were stored in suitably labeled leakproof storage tubes at –20°C or lower until assayed.

Bioanalysis
Serum samples for total and for transferrin-bound iron concentrations were analyzed by MDS Pharma Services (St. Laurent, QU, Canada) according to Good Laboratory Practice guidelines established by the US Food and Drug Administration. SFGC-bound iron was calculated as the difference between the total iron and the transferrin-bound iron.

The analytical methods were based on published methods (7,8) and validated using a validated colorimetric method (9). In brief, transferrin-bound iron dissociates to form ferrous ions at an acidic pH. These ions react with ferrozine (a sulfonated derivative of diphenyltriazine) to produce a water-soluble magenta-colored complex with maximum absorption at 560 nm. The difference in color intensity at this wavelength, before and after the addition of ferrozine, is directly proportional to the serum iron concentration. The iron concentration in the unknown samples can therefore be interpolated from a standard curve that contains known amounts of iron. Total iron in human serum (serum iron and SFGC-bound iron) was quantified in the same manner except that a suitable reducing agent (sodium hydrosulfite) was added to the samples before the addition of ferrozine. The iron derived from SFGC was calculated as the difference between total serum iron and transferrin-bound iron.

The assay for the determination of total (transferrin-bound plus SFGC-bound) iron concentration had a range of 50.0 to 2000.0 µg/dl with a lower limit of quantification of 50.0 µg/dl. The assay for the determination of transferrin-bound iron had a range of 50.0 to 1800.0 µg/dl and a lower limit of quantification of 59.705 µg/dl.

Pharmacokinetic Analysis
The single-dose pharmacokinetics of SFGC were characterized by the determination of the following parameters: Maximum SFGC concentration (Cmax), area under the concentration-time curve (AUC), time to Cmax (Tmax), terminal elimination half-life (t1/2), apparent elimination rate constant (kel), clearance (Cl), and the volume of distribution of SFGC-bound iron (Vd). With the use of noncompartmental analytical modeling, AUC was calculated by the trapezoidal rule up to the last quantified SFGC concentration (AUC0 to t) and thereafter by extrapolation of the terminal elimination phase to infinity (AUC0 to {infty}). Cmax and Tmax were calculated by visual inspection of the concentration-time curves; t1/2 was calculated as ln (2)/kel. Kel was derived by log-linear regression of the terminal portion of the concentration-time curve. No values were reported for kel, Vd, Cl, or t1/2 when there was not a well-characterized terminal log-linear phase in the serum concentration-time curve.

A population pharmacokinetic NONMEM analysis method of SFGC-bound iron that was developed in a previous study in healthy, iron-deficient adults (6) was applied to the SFGC-bound iron concentration data. The analysis used a physiologic-based model with the following four compartments: (1) The central compartment containing drug-bound iron, (2) the liver RES, (3) transferrin-bound iron, and (4) the storage compartment that was essentially the erythrocytes. Application of this NONMEM analysis model was not successful, and a standard two-compartment NONMEM model that was successful and accurate in describing the time course of the SFGC-bound iron concentrations in the pediatric population was developed.

Electrophoretic Separation of Transferrins
The iron forms of transferrin were separated using polyacrylamide gel electrophoresis (PAGE) with samples taken at baseline and at 30, 60, 75, 120, and 360 min and 48 h after the start of the SFGC infusion. PAGE was performed using a modified method of the procedure first described by Mackey and Seal (10) and later modified by Agarwal (11). Eight percent polyacrylamide gels were made using a 19:1 acrylamide/Bis in TBE buffer (0.1 M Tris base, 0.09 M boric acid, 1.6 mM EDTA, pH to 9.1 with 12 N HCl, then to pH 8.4 with granular boric acid) with 6 M urea. All solutions were prepared using 18 mQ water. Gels were poured in Criterion Cassettes with 18 wells (Bio-Rad, Hercules, CA) and loaded with a 15- to 20-µl sample. Serum samples were mixed with equal volume 2% Acrinol (6,9,-Diamino-2-ethoxyacridine lactate monohydrate), spun, decanted, incubated 2 d at 4°C, spun, decanted, and mixed with 2x sample buffer (0.1 M Tris, 0.1 M boric acid, and 2 mM EDTA [pH 8.4]). Gels were run vertically for 2 h at 197 V then stained with 1% Amido Black in methanol/water/acetic acid 4:4:1 and destained in methanol/water/acetic acid 7:5:88. Protein bands were identified by Western blot using anti-human transferrin antibody (Sigma, St. Louis, MO).


   Results
Top
 Abstract
 Introduction
 Concise Methods
 Results
Discussion
 Disclosures
 References
 
Demographics
Sixty-seven patients were enrolled into the iron repletion study and randomly assigned to either the 1.5- or 3.0 mg/kg treatment group. Forty-nine (22 at 1.5 mg/kg; 27 at 3.0 mg/kg) of these patients consented to participate in the pharmacokinetic portion of the study and provided a total of 499 serum samples for pharmacokinetic analysis. The patients who participated in the pharmacokinetic arm of the study were enrolled at 16 study sites located in Mexico (one site, three patients), Poland (eight sites, 15 patients), Russia (five sites, 18 patients), Serbia (one site, eight patients), and the United States (one site, five patients). Table 1 summarizes the demographics of the patients.


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  		Table 1. Patient demographicsa

 
Serum Iron Concentrations and SFGC Pharmacokinetics
The intravenous administration of SFGC during 1 h produced a rapid rise in total serum iron and SFGC-bound iron concentrations followed by a somewhat delayed, slower, and less prominent rise in transferrin-bound iron in both treatment groups (Figure 1). Mean serum iron concentrations (total iron and SFGC-bound iron) rapidly increased in a dosage-dependent manner that was approximately proportional to the intravenously administered SFGC dose (Figure 2).


Figure 1
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  		Figure 1. Serum iron concentrations after sodium ferric gluconate complex (SFGC) infusion: Total iron (•), SFGC-bound iron ({blacksquare}), and transferrin-bound iron ({triangledown}).

 

Figure 2
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  		Figure 2. Ferric gluconate–bound iron concentrations after SFGC infusion at various dosage levels: 1.5 mg/kg (•) and 3.0 mg/kg ({circ}).

 
The single-dose pharmacokinetics of SFGC-bound iron were adequately described using noncompartmental analytical methods (Table 2). Mean SFGC-bound iron pharmacokinetic parameters Cmax, AUC0 to 6 h, and AUC0 to {infty} increased in a dosage-dependent manner that was approximately proportional to the administered SFGC dose. Median serum SFGC-bound iron Tmax occurred at 1 h, characteristic of an intravenous infusion at a constant rate, and corresponded with the ending of the SFGC infusion. The kel, Cl, t1/2, and Vd were similar after infusion of either dosage strength. The apparent Vd was somewhat less than the calculated blood volume (calculated as 79 ml blood volume/kg body wt) in the 1.5-mg/kg treatment group (1.6 versus 2.3 L, respectively) and in the 3.0-mg/kg treatment group (1.9 versus 2.5 L, respectively).


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  		Table 2. SFGC pharmacokinetics by treatment groupa

 
Comparison with Adult Pharmacokinetic Parameters
Concentration versus time curves that were obtained after the 1.5-mg/kg SFGC infusion in pediatrics were of similar shape and magnitude, with similar Cmax values compared with those obtained from a 125-mg/60-min SFGC infusion in healthy but iron-deficient adult volunteers in a previously conducted study (Figure 3) (6). Mean AUC0 to {infty} values were approximately two to three times greater and mean Cl rates were approximately five to six times slower in pediatric patients with ESRD than in the adult volunteers (Table 3).


Figure 3
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  		Figure 3. Pediatric versus adult ferric gluconate–bound iron concentrations after SFGC infusion. Adult dosage, 125 mg (•); pediatric dosage, 1.5 mg/kg ({circ}).

 

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  		Table 3. Comparison of pediatric and adult pharmacokinetic parameters

 
Transferrin Separation and Saturation
The 6% urea polyacrylamide gels showed separation of iron-free transferrin (apo-transferrin), both species of monoferric transferrin as well as diferric transferrin. Using densitometry, the following was demonstrated: (1) With both high (3.0 mg/kg) and low (1.5 mg/kg) doses of SFGC, <10% of the iron was transferred to transferrin 30 min after the infusion had begun, at a time when one half of the full dose of SFGC had been delivered and was present in the serum. (2) In the greatest number of patients, complete transferrin saturation was not reached until 6 h after the start of the infusion and at a time when <5% of drug product was left in the serum. Figure 4 shows representative gels for each dosing schedule. At 6 h after the start of the infusion, the gels from the low-dosage group suggest that three of 16 participants reached close to 100% TSAT, whereas 12 of 18 participants from the high-dosage group showed apparent total transferrin saturation.


Figure 4
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  		Figure 4. Representative polyacrylamide/6% urea gels that demonstrate transferrin saturation (TSAT) for (A) a patient who was given the low-dosage (1.5 mg/kg) infusion and (B) a patient who was given the high-dosage (3.0 mg/kg) infusion. The lanes are identified with the time after start of infusion. The various transferrin species based on iron saturation are indicated. The higher band for monoferric transferrin is iron bound to the C terminus, and the lower band is the N terminus site bound to iron. X, artifact or contaminant and is not transferrin. At 60 min (Tmax for total iron), there is little change from baseline with either dosage. At 6 h after the high dosage, (Tmax for transferrin-bound iron), almost all of the transferrin is diferric. By 48 h, the distribution is back to baseline. Whereas a majority of patients who received high-dosage infusion showed similar qualitatively "total" saturation at 6 h, very few of the patients who received the low-dosage infusion did so.

 

   Discussion
Top
 Abstract
 Introduction
 Concise Methods
 Results
 Discussion
Disclosures
 References
 
Iron deficiency is the most common cause of erythropoietin-resistant anemia in children who receive long-term HD, and, aside from iron dextran, SFGC is the only intravenous iron preparation in the United States that is approved for this indication in the pediatric population (3–5). Although there have been several published reports on this use of this drug in children on HD, this is the first study to describe the pharmacokinetics of SFGC in this population (12,13). Not only is this the first such study in children, but also it is the largest study of SFGC pharmacokinetics for patients of any age on HD; the previously published study of Seligman et al. (6) was performed with adults with normal kidney function.

Our data provide evidence that SFGC follows linear pharmacokinetics at the dosages studied. Cmax, AUC0 to 6 h, and AUC0 to {infty} increased in a dosage-proportional manner, whereas kel, Cl, t1/2, and Vd were similar irrespective of dosage. After the intravenous administration of SFGC, mean serum iron concentrations (total iron and SFGC-bound iron) rapidly increased in a dosage-dependent manner that was approximately proportional to the administered SFGC dose. In contrast, there was a slower and less prominent rise in the concentration of transferrin-bound iron. This delayed rise in transferrin-bound iron, which was qualitatively demonstrated by the gel studies and seemed greater after the higher dosage of SFGC, is reflective of the iron movement in the body whereby SFGC first delivers iron to the RES as opposed to direct transfer from SFGC to transferrin. Iron is then subsequently delivered to transferrin and eventually to the red blood cells and ferritin. The movement of iron directly to transferrin could theoretically result in saturation of transferrin binding sites, the generation of free iron, and worsening of oxidative stress (14,15). The relationship between oxidative stress and cardiovascular disease is particularly important for pediatric HD patients in whom cardiovascular disease is the most common cause of death (16–20). While a greater amount of iron was bound to transferrin after the higher dosage of SFGC, there was no difference in the hemoglobin increase achieved after the high and low dosages of SFGC, respectively, during the recently published clinical study (4). This prompted the recommendation that iron repletion therapy consist of eight 1.5-mg/kg doses of SFGC.

The single-dose pharmacokinetics of SFGC-bound iron in this pediatric ESRD population was adequately described using noncompartmental analytical methods, in contrast to the NONMEM analysis model developed for a healthy, iron-deficient adult population (6). A standard two-compartment NONMEM model was developed after studying the data from 24 of the pediatric patients, by collapsing the three physiologic compartments in the adult model to a single peripheral compartment. This reduced the model to two compartments that successfully and closely described the SFGC-bound iron concentrations (Figure 5). Several possible reasons related to differences in study design might account for the successful convergence of the NONMEM model with the adult data but not with the pediatric data. Although there were more pediatric patients (24 versus 14), there were substantially fewer observations in the pediatric data set. In the adult study, 23 samples were obtained during a 72-h time frame with this sampling schedule repeated at a different, second dose. In our pediatric study, nine samples were obtained during 48 h, and each participant received only one dose of SFGC. Accordingly, the final adult data set included 1068 observations in 14 participants, whereas the pediatric data set consisted of 374 observations in 24 participants. This large difference in the number and time frame of observations, the amount of iron removed by blood sampling (iron loss from blood draws in adults equaled or exceeded iron administered), and the difference in dosing (adults received two of four possible doses, whereas the pediatric participants received one of two possible doses) was likely primarily responsible for the unsuccessful application of the very complicated Seligman model to the pediatric data. Thus, although the inability of the NONMEM model to describe adequately the pediatric pharmacokinetic data may suggest apparent differences in the pharmacokinetics of SFGC-bound iron between the two populations, this conclusion may not be appropriate given the differences between the two study designs


Figure 5
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  		Figure 5. Pharmacokinetic models. (A) The four-compartment model developed from the adult data includes the central compartment (VC) that contains drug-bound iron (Drug) and three physiologic compartments: the reticuloendothelial system in the liver (VRES), transferrin-bound iron (VTBI), and the storage compartment (VS), essentially, the erythrocytes. (CLT, total clearance as iron is incorporated into erythrocytes; CLD, clearance as a result of distribution between VC and VRES as drug-bound iron is taken up into the RES; CLS, clearance as a result of distribution between VS and VRES, as iron is recycled from senescent erythrocytes into the RES.) (B) The standard two-compartment model developed from the pediatric data includes the central compartment (VC) but collapses the three physiologic compartments from the adult model to a single peripheral compartment (VP). (CLT, total clearance; CLD, clearance as a result of distribution between central and peripheral compartments.)

 
Finally, a comparison of the pharmacokinetic parameters that were obtained from the pediatric patient population with ESRD and the pharmacokinetic parameters that were obtained in the earlier study by Seligman et al. (6) of a healthy, iron-deficient adult population revealed similar Cmax values with the administration of similar SFGC dosages; however, compared with the adult values, the mean AUC0 to {infty} values of the children were greater, whereas the mean clearance rates were slower. Although these data might also suggest inherent differences in the pharmacokinetic properties of the two populations, the information should be interpreted with caution because of the major differences (dialysis dependent versus healthy) between the two study populations. Future studies of the adult HD patient population will be necessary to clarify this issue.


   Disclosures
Top
 Abstract
 Introduction
 Concise Methods
 Results
 Discussion
 Disclosures
References
 
B. A. Warady: Scientific Advisor, Watson Pharma. Naomi V. Dahl is an employee of Watson Laboratories.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received February 15, 2007. Accepted June 29, 2007.


   References
Top
 Abstract
 Introduction
 Concise Methods
 Results
 Discussion
 Disclosures
 References
 

  1. National Kidney Foundation: KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis47[Suppl 3] :S1 –S146,2006
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  7. Persijn JP, van der SW, Riethorst A: Determination of serum iron and latent iron-binding capacity (LIBC). Clin Chim Acta35 :91 –98,1971[CrossRef][Medline]
  8. Seligman PA, Schleicher RB: Comparison of methods used to measure serum iron in the presence of iron gluconate or iron dextran. Clin Chem45 :898 –901,1999[Free Full Text]
  9. Iron and Total Iron Binding Capacity: Procedure 565, St. Louis, Sigma Diagnostics,2000
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