Ferrlecit Classification Essay

CLINICAL PHARMACOLOGY

Mechanism Of Action

Ferrlecit is used to replete the body content of iron. Iron is critical for normal hemoglobin synthesis to maintain oxygen transport. Additionally, iron is necessary for metabolism and various enzymatic processes.

Pharmacokinetics

Multiple sequential single dose intravenous pharmacokinetic studies were performed on 14 healthy iron-deficient volunteers. Entry criteria included hemoglobin ≥ 10.5 gm/dL and transferrin saturation ≤ 15% (TSAT) or serum ferritin value ≤ 20 ng/mL. In the first stage, each subject was randomized 1:1 to undiluted Ferrlecit injection of either 125 mg/hr or 62.5 mg/0.5 hr (2.1 mg/min). Five days after the first stage, each subject was rerandomized 1:1 to undiluted Ferrlecit injection of either 125 mg/7 min or 62.5 mg/4 min ( > 15.5 mg/min).

Peak drug levels (Cmax ) varied significantly by dosage and by rate of administration with the highest Cmax observed in the regimen in which 125 mg was administered in 7 minutes (19.0 mg/L). The terminal elimination half-life for drug bound iron was approximately 1 hour. Half-life varied by dose but not by rate of administration. Half-life values were 0.85 and 1.45 hours for the 62.5 mg/4 min and 125 mg/7 min regimens, respectively. Total clearance of Ferrlecit was 3.02 to 5.35 L/h. The AUC for Ferrlecit bound iron varied by dose from 17.5 mg-h/L (62.5 mg) to 35.6 mg-h/L (125 mg). Approximately 80% of drug bound iron was delivered to transferrin as a mononuclear ionic iron species within 24 hours of administration in each dosage regimen. Direct movement of iron from Ferrlecit to transferrin was not observed. Mean peak transferrin saturation returned to near baseline by 40 hours after administration of each dosage regimen.

Pediatrics

Single dose intravenous pharmacokinetic analyses were performed on 48 iron-deficient pediatric hemodialysis patients. Twenty-two patients received 1.5 mg/kg Ferrlecit and 26 patients received 3.0 mg/kg Ferrlecit (maximum dose 125 mg). The mean Cmax, AUC0-∞ , and terminal elimination half-life values following a 1.5 mg/kg dose were 12.9 mg/L, 95.0 mg·hr/L, and 2.0 hours, respectively. The mean Cmax, AUC0-∞, and terminal elimination half-life values following a 3.0 mg/kg dose were 22.8 mg/L, 170.9 mg·hr/L, and 2.5 hours, respectively.

In vitro experiments have shown that less than 1% of the iron species within Ferrlecit can be dialyzed through membranes with pore sizes corresponding to 12,000 to 14,000 daltons over a period of up to 270 minutes. Human studies in renally competent patients suggest the clinical insignificance of urinary excretion.

Clinical Studies

Two clinical studies (Studies A and B) were conducted in adults and one clinical study was conducted in pediatric patients (Study C) to assess the efficacy and safety of Ferrlecit.

Study A

Study A was a three-center, randomized, open-label study of the safety and efficacy of two doses of Ferrlecit administered intravenously to irondeficient hemodialysis patients. The study included both a dose-response concurrent control and an historical control. Enrolled patients received a test dose of Ferrlecit (25 mg of elemental iron) and were then randomly assigned to receive Ferrlecit at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Ferrlecit was given to both dose groups in eight divided doses during sequential dialysis sessions (a period of 16 to 17 days). At each dialysis session, patients in the low-dose group received Ferrlecit 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received Ferrlecit 125 mg of elemental iron over 60 minutes. The primary endpoint was the change in hemoglobin from baseline to the last available observation through Day 40.

Eligibility for this study included chronic hemodialysis patients with a hemoglobin below 10 g/dL (or hematocrit at or below 32%) and either serum ferritin below 100 ng/mL or transferrin saturation below 18%. Exclusion criteria included significant underlying disease or inflammatory conditions or an epoetin requirement of greater than 10,000 units three times per week. Parenteral iron and red cell transfusion were not allowed for two months before the study. Oral iron and red cell transfusion were not allowed during the study for Ferrlecit-treated patients.

The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.

The evaluated population consisted of 39 patients in the low-dose Ferrlecit (sodium ferric gluconate complex in sucrose injection) group (50% female, 50% male; 74% white, 18% black, 5% Hispanic, 3% Asian; mean age 54 years, range 22–83 years), 44 patients in the high-dose Ferrlecit group (50% female, 48% male, 2% unknown; 75% white, 11% black, 5% Hispanic, 7% other, 2% unknown; mean age 56 years, range 20–87 years), and 25 historical control patients (68% female, 32% male; 40% white, 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25–84 years).

The mean baseline hemoglobin and hematocrit were similar between treatment and historical control patients: 9.8 g/dL and 29% and 9.6 g/dL and 29% in low- and high-dose Ferrlecit-treated patients, respectively, and 9.4 g/dL and 29% in historical control patients. Baseline serum transferring saturation was 20% in the low-dose group, 16% in the high-dose group, and 14% in the historical control. Baseline serum ferritin was 106 ng/mL in the low-dose group, 88 ng/mL in the high-dose group, and 606 ng/mL in the historical control.

Patients in the high-dose Ferrlecit group achieved significantly higher increases in hemoglobin and hematocrit than patients in the low-dose Ferrlecit group. See Table 1.

TABLE 1 : Study A: Hemoglobin, Hematocrit, and Iron Studies

 Mean Change from Baseline to Two Weeks After Cessation of Therapy
Ferrlecit 1000 mg IV
(N=44)
Ferrlecit 500 mg IV
(N=39)
Historical Control Oral Iron
(N=25)
Hemoglobin (g/dL)1.1*0.30.4
Hematocrit (%)3.6*1.40.8
Transferrin Saturation (%)8.52.86.1
Serum Ferritin (ng/mL)199132NA
* p < 0.01 versus the 500 mg grou1000 mg IV
(N=44)
500 mg IV
(N=39)
Oral Iron
(N=25)

Study B

Study B was a single-center, non-randomized, open-label, historicallycontrolled, study of the safety and efficacy of variable, cumulative doses of intravenous Ferrlecit in iron-deficient hemodialysis patients. Ferrlecit administration was identical to Study A. The primary efficacy variable was the change in hemoglobin from baseline to the last available observation through Day 50.

Inclusion and exclusion criteria were identical to those of Study A as was the historical control population. Sixty-three patients were evaluated in this study: 38 in the Ferrlecit-treated group (37% female, 63% male; 95% white, 5% Asian; mean age 56 years, range 22– 84 years) and 25 in the historical control group (68% female, 32% male; 40% white, 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25–84 years).

Ferrlecit-treated patients were considered to have completed the study per protocol if they received at least eight Ferrlecit doses of either 62.5 mg or 125 mg of elemental iron. A total of 14 patients (37%) completed the study per protocol. Twelve (32%) Ferrlecit-treated patients received less than eight doses, and 12 (32%) patients had incomplete information on the sequence of dosing. Not all patients received Ferrlecit at consecutive dialysis sessions and many received oral iron during the study.

Cumulative Ferrlecit Dose (mg of elemental iron)62.5250375562.5625750100011251187.5
Patients (#)11211041261

Baseline hemoglobin and hematocrit values were similar between the treatment and control groups, and were 9.1 g/dL and 27.3%, respectively, for Ferrlecit-treated patients. Serum iron studies were also similar between treatment and control groups, with the exception of serum ferritin, which was 606 ng/mL for historical control patients, compared to 77 ng/mL for Ferrlecit-treated patients.

In this patient population, only the Ferrlecit-treated group achieved increase in hemoglobin and hematocrit from baseline. See Table 2.

TABLE 2 : Study B: Hemoglobin, Hematocrit, and Iron Studies

 Ferrlecit
(N=38) change
Ural Iron
(N=25) change
Hemoglobin (g/dL)1.30.4
Hematocrit (%)3.80.2
Transferrin Saturation (%)6.71.7
Serum Ferritin (ng/dL)73-145

Study C

Study C was a multicenter, randomized, open-label study of the safety and efficacy of two Ferrlecit dose regimens (1.5 mg/kg or 3.0 mg/kg of elemental iron) administered intravenously to 66 iron-deficient (transferring saturation < 20% and/or serum ferritin < 100 ng/mL) pediatric hemodialysis patients, 6 to 15 years of age, inclusive who were receiving a stable erythropoietin dosing regimen.

Ferrlecit at a dose of 1.5 mg/kg or 3.0 mg/kg (up to a maximum dose of 125 mg of elemental iron) in 25 mL 0.9% sodium chloride was infused intravenously over 1 hour during each hemodialysis session for eight sequential dialysis sessions. Thirty-two patients received the 1.5 mg/kg dosing regimen (47% male, 53% female; 66% Caucasian, 25% Hispanic, and 3% Black, Asian, or Other; mean age 12.3 years). Thirty-four patients received the 3.0 mg/kg dosing regimen (56% male, 44% female; 77% Caucasian, 12% Hispanic, 9% Black, and 3% Other; mean age 12.0 years).

The primary endpoint was the change in hemoglobin concentration from baseline to 2 weeks after last Ferrlecit administration. There was no significant difference between the treatment groups. Improvements in hematocrit, transferrin saturation, serum ferritin, and reticulocyte hemoglobin concentrations compared to baseline values were observed 2 weeks after the last Ferrlecit infusion in both the 1.5 mg/kg and 3.0 mg/kg treatment groups (Table 3).

TABLE 3 : Study C: Hemoglobin, Hematocrit, and Iron Status

 Mean Change From Baseline to Two Weeks After Cessation of Therapy in Patients Completing Treatment
1.5 mg/kg Ferrlecit
(N=25)
3.0 mg/kg Ferrlecit
(N=32)
Hemoglobin (g/dL)0.80.9
Hematocrit (%)2.63.0
Transferrin Saturation (%)5.510.5
Serum Ferritin (ng/mL)192314
Reticulocyte Hemoglobin Content (pg)1.31.2

The increased hemoglobin concentrations were maintained at 4 weeks after the last Ferrlecit infusion in both the 1.5 mg/kg and the 3.0 mg/kg Ferrlecit dose treatment groups.

1. Introduction

Iron is an essential component of every cell in the body. Although best known for its critical role in the transport and storage of oxygen (in hemoglobin and myoglobin, respectively), within a large variety of enzymes iron also acts as a carrier for electrons, a catalyst for oxygenation, hydroxylation, and is necessary for cellular growth and proliferation. Iron supplements are widely administered to treat iron deficiency anemia, particularly in chronic diseases such as kidney disease [1], heart failure [2] or inflammatory bowel disease [3]. Without a sufficient supply of iron, hemoglobin cannot be synthesized and the number of erythrocytes in the blood cannot be maintained at an adequate level [4]. However, because of the ubiquity of iron, its compartmentalized sites of action, and its complex metabolism, usual pharmacokinetics measurements such as serum concentration are largely irrelevant when evaluating the bioavailability and efficacy of iron preparations [5]. As such, pharmacokinetics and pharmacodynamics assessments of iron preparations cannot be based on the standard principles that apply to non-endogenous drugs.

Understanding the metabolism of iron underpins any consideration of its pharmacology (Figure 1). Iron usually exists in the ferrous (Fe2+) or ferric (Fe3+) state, but since Fe2+ is readily oxidized to Fe3+, which in neutral aqueous solutions rapidly hydrolyzes to insoluble iron(III)-hydroxides, iron is transported and stored bound to proteins. Effective binding of iron is essential not only to ensure that it is available where and when required, but also because Fe2+ can catalyze the formation of reactive oxygen species, which cause oxidative stress, damaging cellular constituents. Three key proteins regulate the transport and storage of iron. Transferrin transports iron in the plasma and the extracellular fluid. The transferrin receptor, expressed by cells that require iron and present in their membranes, binds the transferrin di-iron complex and internalizes it into the cell. Ferritin is an iron-storage protein that sequesters iron keeping it in a readily available form. About 60% of iron is found in the erythrocytes within hemoglobin [6], the oxygen transport protein. The remainder is found in myoglobin in the muscles, in a variety of different enzymes (‘heme’ and ‘non-heme’), and in storage form. Most stored iron is in the form of ferritin, found in the liver, bone marrow, spleen and muscles. Serum iron (i.e., iron bound to transferrin) represents only a very small proportion of total body iron (<0.2%) [7]. Moreover, the relationship between physiological iron compartments is highly dynamic: Erythrocytes are broken down in the liver and in the spleen, and new red blood cells are produced in the bone marrow. The total serum iron pool is approximately 4 mg, but the normal daily turnover is not greater than 30 mg [7], such that minor changes in serum level due to exogenous iron administration are clinically meaningless. In this setting, conventional measurements of serum iron concentration provide no relevant information about the availability of functional iron for physiological processes, and other evaluation strategies must be pursued.

2. The Pharmacokinetics of Iron

A primary aim of pharmacokinetics analyses is to determine bioavailability, defined by the European Medicines Agency as ‘the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action’ [8]. Typically, bioavailability is assessed based on the serum concentration of the administered product. This model only applies, however, if there is a classical drug-receptor interaction on cell membranes such that efficacy correlates well with the serum concentration of the drug. In the case of iron, the primary site of action is the erythrocyte, with iron storage sites of secondary relevance.

Several definitions have been proposed for iron bioavailability (reviewed in Wienk et al. [9]), but the consensus is that it should be a quantifiable measure of the proportion of total iron that is absorbed and metabolized, i.e. that is incorporated into hemoglobin [9]. As a consequence, serum concentration is not relevant. Notably, the process of erythropoiesis takes 3–4 weeks [4], such that iron utilization from the time of administration only peaks after approximately 2–3 weeks [10] and short-term area under the curve (AUC) values of serum iron (e.g., over 8 hours) are of much less relevance than long-term (e.g., 3-month) values for iron uptake by erythrocytes. The amount of iron in the serum represents only a small part of the iron that is transferred to the site of action, which is not proportional to the peak serum concentration (Cmax) or to the AUC value but to the rates of transfer and elimination to and from the serum. Thus, other approaches to pharmacokinetics assessment of iron are clearly required [11-13].

2.1. Pharmacokinetics of iron after intravenous application

Iron is administered intravenously in the form of iron carbohydrate complexes consisting of a mineral core, composed of polynuclear iron(III)-hydroxide surrounded by the carbohydrate ligand [14]. The main function of the ligand is to stabilize the complex and to protect it against further polynuclearization. Examples include Venofer® (iron sucrose), Ferinject® (ferric carboxymaltose), Ferrlecit® (sodium ferric gluconate in sucrose, for injection) and various iron dextran formulations. Iron carbohydrate complexes of this type behave as prodrugs, since the iron has to be released from the iron(III)-hydroxide core. According to the proposed mechanism, after administration, the stable complexes such as ferric carboxymaltose and iron dextran are taken up by endocytosis by macrophages of the reticuloendothelial system (RES) [14]. In a further step, the endosome fuses with a lysosome and the acidic and reducing environment in the endolysosome leads to cleavage of iron from the complex. The Fe2+ generated is transported by the divalent metal transporter 1 (DMT1) across the endolysosomal membrane to enter the labile iron pool within the macrophage cytoplasm. From there, it can be incorporated into ferritin and remain transiently stored within the macrophage or can be transported out of the macrophage by the transmembrane protein ferroportin (as Fe2+). The exported Fe2+ is immediately oxidized by ceruloplasmin to Fe3+ which is sequestered by transferrin for transport in the serum to the sites of utilization, e.g., in the bone marrow for hemoglobin synthesis or in the liver for storage in ferritin.

In the case of less stable preparations, however, this highly regulated process of iron release from carbohydrate complexes can be disrupted. Here, release of significant amounts of labile iron from the complex can lead to saturation of transferrin and, thus, to significant amounts of non-transferrin bound iron (NTBI), particularly if high doses are administered. This weakly bound Fe3+ is readily taken up in an unregulated way by cells of the endocrine system, the heart, and the liver, where it can induce oxidative stress by catalyzing lipid peroxidation and reactive oxygen species formation [15].

In general, complexes can be classified as labile or robust (kinetic variability, i.e. how fast can ligands coordinated to the iron be exchanged) and weak or strong (thermodynamic variability, i.e. how strongly are the ligands bound to the iron, and thus, how much energy is required to dissociate a ligand from the iron), or any intermediate state (Table 1) [7]. The reactivity of each complex correlates inversely with its molecular weight, i.e. larger complexes are less prone to release significant amounts of labile iron or react directly with transferrin [14,17]. Type I complexes such as iron dextran preparations (Imferon®, Cosmofer®, InFeD®, Dexferrum®) or ferric carboxymaltose (Ferinject®) have a high molecular weight and a high structural homogeneity, and, thus, deliver iron from the complex to transferrin in a regulated way via macrophages endocytosis and subsequent controlled export [7,10]. Such complexes can be administered intravenously and are clinically well-tolerated even at high doses [17]. Type II complexes (iron sucrose complexes such as Venofer®) are semi-robust and moderately strong, and release larger amounts of weakly bound iron in the blood. Thus, larger amounts of iron are taken up directly by transferrin and other proteins, and only the iron core is taken up via endocytosis by the macrophages of the reticuloendothelial system. Despite the lower molecular weight and complex stability compared to Type I complexes, Type II complexes are still suited for intravenous application. Nevertheless, the maximal single doses are significantly lower and the administration times drastically longer. Type III and IV complexes, including sodium ferric gluconate (Ferrlecit®) and iron(III)-citrate + iron(III)-sorbitol + iron dextrin (Jectofer®), have variable amounts of low molecular weight components (<18,000 Daltons) and are characteristically labile and weak [17]. In general, intravenous use of preparations containing large amounts of complexes with a molecular weight below 18,000 Daltons should only be undertaken with care [17]. These types of iron complexes are likely to generate large amounts of NTBI, which may then bind to various types of proteins – only if they are administered in small doses is the iron taken up primarily by macrophages (endocytosis). Moreover, all iron complexes with molecular weight below 18,000 Daltons are subject to undesirable renal elimination [17].

Figure 2 illustrates the results of an in vitro study that compares the relative reactivity of Ferinject®, Venofer® and Ferrlecit® towards apotransferrin. In this experiment, apotransferrin was incubated with different amounts of the three intravenous iron preparations at a final concentration equivalent to that expected in the serum of an adult patient after injection of ∼200 or ∼2,000 mg of iron. It is noteworthy that Ferinject® has a significantly lower reactivity than the two other complexes. Even at a dose equivalent to ∼2,000 mg iron, Ferinject® does not induce full saturation of transferrin. Weakly bound low molecular weight components result in transferrin saturation and the consequent oxidative stress induced by NTBI leads to adverse events such as hypotension, nausea, vomiting, abdominal and lower back pain, peripheral edema and a metallic taste [19].

The molecular weight of the intravenous iron carbohydrate complexes strongly influences not only the rate of release of iron from the core but also the rate of clearance from the plasma [14]. In fact, Type I complexes have a long half-life of elimination, e.g., Ferinject® 7–12 hours and iron dextran 1–3.5 days (dose-dependent), compared to an elimination half-life of 5–6 hours for iron sucrose (Venofer®) [20] and <4 hours for Types III and IV [7] (e.g. Ferrlecit® 1–1.5 hours [21]). The pharmacokinetics parameters of different intravenous iron preparations have been measured in separate Phase I studies under similar conditions (Table 2) [20–22,24,25]. Based on these parameters, we calculated the normalized AUC after intravenous application of a dose of 100 mg iron for the various iron carbohydrate complexes (Table 2). The results clearly show that AUC is strongly influenced by the terminal elimination rate, which is dependent on the molecular weight of the complex, and not by the dose (Table 2). Moreover, the standardized elimination curves depicted in Figure 3, calculated based on the values of the terminal elimination rates given in Table 2, clearly show the negative correlation between AUC and the elimination rate constants.

Thus, mean serum concentration and AUC do not increase linearly with the dose of injected iron but are inversely correlated with the elimination rates [22,26]. Examination of the total serum iron concentration curves after intravenous application revealed that the elimination of iron from the serum can be explained with an overlap (superimposition) of a zero-order (constant rate) and a first-order elimination function [14,20,24]. This model explains the non-linear relation between the administered dose and the AUC value [12]. By using an open two-compartment model system with an underlying baseline level as well as an underlying Michaelis-Menten term, the serum iron level can be calculated according to the following formula [20]:

where C(t) is the time-dependent serum iron concentration, a, b, α and β are hybrid constants, CB is the iron pre-dose level and k0t is the Michaelis-Menten term. The final distribution volume is normally about 3 liters for a 70 kg person. With the help of k0, the amount of iron taken up by macrophages and/or the iron transferred by transferrin to other compartments can be calculated. From the dose (D) and the difference between the first post-dose C0 and pre-dose level CB, the volume of distribution of the central compartment Vc can be determined.

2.2. Pharmacokinetics of iron after oral application

Absorption of iron from the gut is carefully regulated. Because there is no active excretory process for iron once it has entered the bloodstream, the body's control of iron levels is undertaken at the level of the enterocyte. Iron in food, in the form of Fe3+, is reduced to Fe2+ by duodenal cytochrome b (Dcyt b) in the enterocyte membrane then imported by DMT1 into the enterocyte cytoplasm, where it can either be stored as ferritin or be exported to the serum via the basolateral transport protein ferroportin [27]. This export protein is coupled to multicopper oxidases (hephaestin in the membrane or ceruloplasmin in the serum), which oxidize Fe2+ to Fe3+, which finally is tightly bound to transferrin [27]. The mechanism of uptake of heme iron, derived from meat, is not well understood. It has been proposed that the enterocyte membrane also contains a protein that can transport heme iron from the gut lumen into the cytosol (HCP1) [28]. However, the same protein has later been shown to be responsible for folate transport in the intestine, with a significantly higher affinity [29–31]. In the enterocyte, Fe2+ is released from the heme in a process catalyzed by heme oxygenase [32] and enters the same cytosolic pool as non-heme iron.

A typical diet contains approximately 10–20 mg iron/day, but the fixed-rate physiological uptake route allows for absorption of only up to 5 mg at a time [13,33]. A therapeutic oral iron dose of, for example, 100 mg, thus largely exceeds the amount that can be taken up via the active absorption pathway. Due to the physico-chemical properties of ferrous salts, passive uptake occurs through the paracellular route [33] such that a portion of the Fe2+ in the gut is absorbed directly by the blood. Under normal circumstances, transferrin in the blood is approximately one-third saturated [7]. However, under the pressure of passive diffusion, transferrin becomes saturated and NTBI circulates in the plasma, is taken up via an unregulated mechanism by endocrine and heart cells, resulting in oxidative stress reactions within these tissues. With rapidly absorbed preparations, NTBI can be observed even before transferrin is fully saturated.

Figure 4 illustrates the quantification of NTBI in serum samples from adult volunteers with normal iron stores after oral administration of 100 mg iron in the form of ferrous salts [34]. NTBI concentrations of up to 9 μM were observed within the first four hours post-dose even though transferrin saturation (TSAT) was below 100%. Significant levels of NTBI were detected even at lower doses, e.g., 10 mg iron as ferrous ascorbate or ferrous glycine sulfate [34]. In the same study, it was reported that iron(III)-polymaltose at a dose of 150 mg iron resulted in a maximal NTBI concentration of only 0.7 μM, close to the detection limit of the assay that was used [34]. Interestingly, a similar study showed that significant levels of NTBI are also produced when oral iron preparations based on ferrous salts are taken with food [35]. As the iron dose given in the form of ferrous salts increases, the proportion of iron absorbed through the passive paracellular route increases, such that NTBI rises [34], consistent with the dose-related nature of side effects associated with oral iron therapy [36]. Even passive absorption, however, can become saturated such that ever-increasing doses of oral iron do not result in proportionately higher AUC, a finding demonstrated by Ekenved and coworkers following administration of 25, 50, and 100 mg iron as ferrous sulfate solution (Figure 5) [37]. A linear pharmacokinetics model can therefore be excluded [13]. Thus, a maximum serum iron increase of, for instance, 20 μmol/L can correspond to intestinal iron absorption of between 3.5 and 17 mg [37,38].

If results from other studies are used, this variance will increase even more [39]. In contrast, Heinrich et al. [40] reported a somehow better correlation between iron absorption and the serum iron concentration measured 3 h after a dose of 100 mg iron on an empty stomach. However, the conclusion of the authors is that the serum iron measurement gives only semi-quantitative information on the bioavailability of therapeutic iron preparations [40

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