Use of intravenous iron supplementation in chronic kidney disease: an update.

Iron deficiency is an important clinical concern in chronic kidney disease (CKD), giving rise to iron-deficiency anemia and impaired cellular function. Oral supplementation, in particular with ferrous salts, is associated with a high rate of gastrointestinal side effects and is poorly absorbed, a problem that is avoided with intravenous iron. The most stable intravenous iron complexes (eg, iron dextran, ferric carboxymaltose, ferumoxytol, and iron isomaltoside 1000) can be given in higher single doses and more rapidly than less stable preparations (eg, sodium ferric gluconate). Iron complexes that contain dextran or dextran-derived ligands can cause dextran-induced anaphylactic reactions, which cannot occur with dextran-free preparations such as ferric carboxymaltose and iron sucrose. Test doses are advisable for conventional dextran-containing compounds. Iron supplementation is recommended for all CKD patients with anemia who receive erythropoiesis-stimulating agents, whether or not they require dialysis. Intravenous iron is the preferred route of administration in hemodialysis patients, with randomized trials showing a significantly greater increase in hemoglobin levels for intravenous versus oral iron and a low rate of treatment-related adverse events. In the nondialysis CKD population, the erythropoietic response is also significantly higher using intravenous versus oral iron, and tolerability is at least as good. Moreover, in some nondialysis patients intravenous iron supplementation can avoid, or at least delay, the need for erythropoiesis-stimulating agents. In conclusion, we now have the ability to achieve iron replenishment rapidly and conveniently in dialysis-dependent and nondialysis-dependent CKD patients without compromising safety.

The pharmacokinetics and pharmacodynamics of iron preparations.

Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast to conventional drugs, no drug-receptor interaction takes place. Notably, the process of erythropoiesis, i.e., formation of new erythrocytes, takes 3-4 weeks. Accordingly, serum iron concentration and area under the curve (AUC) are clinically irrelevant for assessing iron utilization. Iron can be administered intravenously in the form of polynuclear iron(III)-hydroxide complexes with carbohydrate ligands or orally as iron(II) (ferrous) salts or iron(III) (ferric) complexes. Several approaches have been employed to study the pharmacodynamics of iron after oral administration. Quantification of iron uptake from radiolabeled preparations by the whole body or the erythrocytes is optimal, but alternatively total iron transfer can be calculated based on known elimination rates and the intrinsic reactivity of individual preparations. Degradation kinetics, and thus the safety, of parenteral iron preparations are directly related to the molecular weight and the stability of the complex. High oral iron doses or rapid release of iron from intravenous iron preparations can saturate the iron transport system, resulting in oxidative stress with adverse clinical and subclinical consequences. Appropriate pharmacokinetics and pharmacodynamics analyses will greatly assist our understanding of the likely contribution of novel preparations to the management of anemia.

The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose.

An ideal preparation for intravenous iron replacement therapy should balance effectiveness and safety. Compounds that release iron rapidly tend to cause toxicity, while large molecules can induce antibody formation and cause anaphylactic reactions. There is therefore a need for an intravenous iron preparation that delivers appropriate amounts of iron in a readily available form but with minimal side effects and thus with an excellent safety profile. In this paper, a review is given on the chemistry, pharmacology, and toxicology of ferric carboxymaltose (FCM, Ferinject), a stable and robust complex formulated as a colloidal solution with a physiological pH. The complex is gradually taken up mainly from the hepatic reticulo-endothelial system (RES), followed by effective delivery of iron to the endogeneous transport system for the haem synthesis in new erythrocytes, as shown in studies on the pharmacodynamics and pharmacokinetics with radio-labelled FCM. Studies with radio-labelled FCM also demonstrated a barrier function of the placenta and a low transfer of iron into the milk of lactating rats. Safety pharmacology studies indicated a favourable profile with regard to cardiovascular, central nervous, respiratory, and renal toxicity. A high maximum non-lethal dose was demonstrated in the single-dose toxicity studies. Furthermore, based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Reproductive and developmental toxicity studies did not reveal any direct or indirect harmful effects. No genotoxic potential was found in in vitro or in vivo studies. Moreover, antigenicity studies showed no cross-reactivity of FMC with anti-dextran antibodies and also suggested that FCM does not possess sensitizing potential. Lastly, no evidence of irritation was found in local tolerance studies with FCM. This excellent toxicity profile and the high effectiveness of FCM allow the administration of high doses as a single infusion or bolus injection, which will enhance the cost-effectiveness and convenience of iron replacement therapy. In conclusion, FCM has many of the characteristics of an ideal intravenous iron preparation.

Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia.

Iron-deficiency anaemia (IDA) represents a major burden to public health worldwide. The therapeutic aim for patients with IDA is to return iron stores and haemoglobin (Hb) levels to within the normal range using supplemental iron therapy and erythropoiesis-stimulating agents. Oral and previous intravenous (i.v.) iron formulations have a number of disadvantages, including immunogenic reactions, oxidative stress, low dosages, long administration times and the requirement for a test dose. Ferric carboxymaltose (FCM, Ferinject) is a novel, next-generation i.v. iron formulation with the potential to overcome these limitations. In this single-centre, randomized, double-blind, placebo-controlled study, the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of single, escalating doses of FCM were investigated. Four ascending doses were investigated in a total of 24 patients with mild IDA (defined as serum ferritin < 20 microg/l and transferrin saturation [TfS] < 16%): 100 mg iron as FCM given as an i.v. bolus injection, and 500, 800 and 1000 mg iron as FCM given as an i.v. infusion over 15 min. At each dose level six patients received FCM and two received placebo. The decision to escalate to the next dose was based on evaluation of safety and tolerability data from the previous dose. The maximum duration of the study was 5 weeks from screening to final assessment. Assessments were made of PK iron-status parameters up to 168 h post-dose. Safety assessments included incidence of adverse events (AEs), clinical laboratory parameters and vital signs. PK and PD parameters were analysed using descriptive statistics. All analyses were performed on the safety population, which included all patients who received > or = 1 dose of study medication. Seventy-seven patients were screened and, of these, 32 male and female patients with pre-study Hb between 9.2 and 11.9 g/dl and serum ferritin < 20 microg/l were included in the study. Two patients had TfS > 16% (19.2% and 17.2%); both patients were considered by the investigator to be eligible for inclusion. Compared with placebo, a rapid, dose-dependent increase in total serum iron was observed across all dose groups. Mean (standard deviation) maximum total serum iron levels ranged between 36.9 (4.4) and 317.9 (42.3) microg/ml in the 100 and 1000 mg groups. Concentration-time curves of total serum iron continuously declined for up to 24 and 72 h post-dose in the 100 and 500-1000 mg groups, respectively. Non-compartmental analysis of PK parameters was truncated at 24 h (100 mg) and 72 h (500-1000 mg doses). A dose-dependent, but not dose-linear, increase in serum ferritin was seen in all treatment groups compared with placebo, with peak levels of a 23-210-fold increase above baseline occurring 48-120 h postdose. Iron-binding capacity was transiently almost fully utilized after doses of 500, 800 and 1000 mg (TfS > 95%). No meaningful changes in serum transferrin or serum transferrin receptor concentrations were observed during this study. The elimination pattern for FCM appeared to be mono-exponential; FCM was cleared from serum with a terminal halflife of approximately 7.4-12.1 h. The percentage of FCM excreted in urine was negligible (0.0005%). FCM was well tolerated; a total of 19 AEs were reported by 8/32 patients (25%), of which three were considered by the investigator to be related to FCM: nausea and vomiting (one patient [100 mg]), and headache (one patient [1000 mg]). The incidence of AEs did not increase with dose. No severe or serious AEs, or deaths occurred. FCM had no significant effect on laboratory safety parameters or vital signs. This study satisfactorily characterized the PK/PD parameters of single doses of 100, 500, 800 and 1000 mg iron as FCM. The majority of FCM was utilized or eliminated within 24 h of administration of a 100 mg dose and within 72 h of a 500-1000 mg dose. FCM was generally well tolerated across all doses in patients with mild IDA.

Pharmacodynamics and safety of ferric carboxymaltose: a multiple-dose study in patients with iron-deficiency anaemia secondary to a gastrointestinal disorder.

This multiple-dose Phase I/II study provided pharmacodynamics and pharmacokinetics data on the therapeutic benefit of ferric carboxymaltose (FCM, Ferinject) and evaluated the safety and tolerability of this intravenous (i.v.) iron preparation. Two doses of iron as FCM were given as i.v. infusion over 15 min, 500 mg iron given once weekly for up to 4 weeks (Cohort 1) or 1000 mg iron weekly for 2 weeks (Cohort 2), in patients with a total requirement > or = 1000 mg iron (total cumulative maximum dose < or = 2000 mg iron). Adults with moderate to severe, stable iron-deficiency anaemia (IDA) (haemoglobin [Hb] < or = 11.0 g/dl, serum ferritin < 100 microg/l, transferrin saturation [TSAT] < 16%) due to a gastrointestinal (GI) disorder were included. Pharmacodynamics variables: proportion of patients achieving values within the reference range for Hb (men: 14.0-18.0 g/dl, women: 12.0-16.0 g/dl), serum ferritin (20-500 microg/l), TSAT (16-45%) and proportion of patients with an increase in Hb of at least 2.0 g/dl. Pharmacokinetics variables: total serum iron levels at time of maximum serum iron concentration during the fast elimination phase and at trough time-points. Safety assessments: the incidence of adverse events (AEs) and changes in vital signs, physical examinations, and clinical laboratory parameters. In Cohorts 1 and 2, 14/20 (70%) versus 19/26 (73%) of patients completed the study. Individual calculated iron deficits were 1000-2100 mg. The mean cumulative dose of FCM in Cohorts 1 and 2 was 1800 mg and 1563 mg iron, respectively. At baseline, patients in both cohorts had similar Hb levels (mean 8.7 g/dl in both cohorts). More than 97% of patients demonstrated a clinically meaningful increase in Hb levels (> or = 1.0 g/dl) during the study. By the week 4 follow-up visit, an increase of at least 2.0 g/dl was achieved by 15/20 (75%) and by 19/26 (73.1%) patients in Cohorts 1 and 2, respectively, and the mean increase in Hb was 3.2 g/dl in Cohort 1 and 3.3 g/dl in Cohort 2. By day 28, 3/6 (50%) patients in Cohort 1 had achieved normal Hb levels, and by the 4-week post-treatment followup visit 7/19 patients (37%) in Cohort 1 and 12/25 (48%) in Cohort 2 had reached Hb levels within the reference range. Serum ferritin levels increased rapidly at the start of treatment and remained in the reference range throughout the study; increases were greater in Cohort 2. Mean baseline TSAT values were similar in both cohorts (24.2% in Cohort 1, 20.7% in Cohort 2), and were within the reference range at the week 4 follow-up visit for 41.0 and 39.1% of the patients in Cohorts 1 and 2, respectively. The incidence of AEs occurring after the first administration of FCM (treatment-emergent AEs, TEAE) was generally low and similar in Cohorts 1 (11/20 [55.0%]) and 2 (13/26 [50.0%]). Most TEAEs were mild; only 2/ 20 patients (10.0%) in Cohort 1 and 3/26 (11.5%) in Cohort 2 had TEAEs of moderate intensity. There were no AEs of severe intensity, serious AEs, or deaths. Most AEs were considered by the investigator to be unrelated or unlikely to be related to the study medication. Since accumulation of serum iron was not observed, a dosing interval of 3-4 days (500 mg iron) or 1 week (1000 mg iron) was demonstrated to be adequate. The increase in serum ferritin and TSAT at the 4-week follow-up visit is indicative of a repletion of the iron stores. The results suggest that doses up to 1000 mg i.v. iron administered as FCM over 15 min arewell tolerated and effective in the treatment of patients with IDA due to a GI disorder.

Effects of oral iron(III) hydroxide polymaltose complex supplementation on hemoglobin increase, cognitive function, affective behavior and scholastic performance of adolescents with varying iron status: a single centre prospective placebo controlled study.

OBJECTIVE: To assess the effects of iron supplementation on iron status, cognitive function, affective behavior and scholastic performance in adolescents with varying iron status. METHODS: Adolescents of both sexes with varying iron status were allocated to four treatment groups by using inclusion criteria. Three of the four groups (iron deficient anemic, iron deficient and control supplement) received iron(III) hydroxide polymaltose complex (IPC, Maltofer) containing 100 mg of elemental iron 6 days a week for 8 months, while the fourth group (control placebo) was given a placebo. Hematological parameters, cognitive function, affective behavior and scholastic performance were assessed at baseline, 4 months and 8 months of supplementation. RESULTS: Cognitive and scholastic performance test scores for the three supplemented groups increased from baseline to 4 months and from 4 months to 8 months (with concomitant increases in hematological parameters), whereas no increase was observed in the placebo group. No increase was seen in affective behavior scores for any of the groups during or after supplementation. CONCLUSIONS: IPC supplementation for eight months yielded significant improvements in cognitive function and scholastic performance in Indian adolescents with and without iron deficiency and anemia.

Effects of oral supplementation with iron(III) hydroxide polymaltose complex on the hematological profile of adolescents with varying iron status.

OBJECTIVE: To assess the effects of supplementation with oral iron(III) hydroxide polymaltose complex on the iron status of adolescents with and without iron deficiency and anemia. METHOD: Adolescents of both sexes with varying iron status were allocated to four treatment groups by using inclusion criteria. Three of the four groups received iron(III) hydroxide polymaltose complex (IPC, Maltofer) containing 100 mg of iron 6 days a week for 8 months. The fourth group was given a placebo. Hematological parameters were assessed at the baseline and after 4 and 8 months of supplementation. RESULTS: IPC supplementation resulted in a significant increase in iron parameters in all the three supplemented groups including correction of iron deficiency and anemia along with improvement in storage iron after 8 months. No side effects were noted in any of the supplemented subjects. CONCLUSIONS: IPC supplementation improved the iron status of adolescents with and without iron deficiency and anemia. These data provide evidence that IPC is an easy-to-administer and well tolerated compound which can improve and normalize the iron status of iron deficient and anemic patients.

Interactions between iron(III)-hydroxide polymaltose complex and commonly used drugs / simulations and in vitro studies.

Under physiological conditions, ferric ions are essentially insoluble because of the formation of polynuclear hydroxo-bridged complexes. Ferrous ions are more soluble but may produce hydroxyl radicals on reaction with hydrogen peroxide. Chelation of ferric and ferrous ions with organic ligands may prevent these undesirable reactions. Alternatively, iron(III)-hydroxide/oxide can be stabilized and solubilized by tight interactions with carbohydrates. The data presented in this work show that, because of its physicochemical properties, the iron(III)-hydroxide polymaltose complex (IPC, Maltofer) does not interact with the active ingredients of commonly used drugs such as acetylsalicylic acid (CAS 50-78-2), tetracycline hydrochloride (CAS 64-75-5), calcium hydrogen-phosphate (CAS 7757-93-9), methyl-L-dopa sesquihydrate (CAS 41372-08-1), and magnesium-L-aspartate hydrochloride (CAS 28184-71-6). In contrast, as confirmed by calculations using thermodynamic parameters, FeCl3 x 6H2O (CAS 10025-77-1) can form different types of complexes with these substances. Moreover, the data show that under aerobic conditions high concentrations of ascorbic acid (CAS 50-81-7) can lead to mobilization of iron from IPC and, thus, support the observation that orange juice slightly increases the uptake of iron from IPC.

Interactions between iron(III)-hydroxide polymaltose complex and commonly used medications / laboratory studies in rats.

Simple iron salts, such as iron sulphate, often interact with food and other medications reducing bioavailability and tolerability. Iron(III)-hydroxide polymaltose complex (IPC, Maltofer) provides a soluble form of non-ionic iron, making it an ideal form of oral iron supplementation. The physicochemical properties of IPC predict a low potential for interactions. The effects of co-administration with aluminium hydroxide (CAS 21645-51-2), acetylsalicylic acid (CAS 50-78-2), bromazepam (CAS 1812-30-2), calcium acetate (CAS 62-54-4), calcium carbonate (CAS 471-34-1), auranofin (CAS 34031-32-8), magnesium-L-aspartate hydrochloride (CAS 28184-71-6), methyldopa sesquihydrate (CAS 41372-08-1), paracetamol (CAS 103-90-2), penicillamine (CAS 52-67-5), sulfasalazine (CAS 599-79-1), tetracycline hydrochloride (CAS 64-75-5), calcium phosphate (CAS 7757-93-9) in combination with vitamin D3 (CAS 67-97-0), and a multi-vitamin preparation were tested in rats fed an iron-deficient diet. Uptake of iron from radiolabelled IPC with and without concomitant medications was compared. None of the medicines tested had a significant effect on iron uptake. Iron-59 retrieval from blood and major storage organs was 64-76% for IPC alone compared with 59-85% following co-administration with other medications. It is concluded that, under normal clinical conditions, IPC does not interact with these medications.

Effect of an oral iron(III)-hydroxide polymaltose complex on tetracycline pharmacokinetics in patients with iron deficiency anemia.

The study was carried out as an open-label, but laboratory-blind, single-dose, single-centre, randomized, two-period crossover study. Twenty-two patients with iron deficiency anemia completed the study. The study consisted of two treatment phases of 36 h, separated by a washout period of between 6 and 14 days. The two treatments were given orally. The reference treatment was tetracycline (CAS 60-54-8) alone (2 x 250 mg capsules) and the test treatment was iron(III)-hydroxide polymaltose complex (IPC, Maltofer) together with tetracycline (2 x 250 mg capsules). IPC had no pharmacokinetic effect on the rate of absorption of tetracycline. With concomitant administration of tetracycline and IPC sufficiently high tetracycline concentrations, to ensure bacteriostasis, will be reached. An inhibitor effect of IPC to the tetracycline absorption, as it is known for ferrous salts, could not be observed.

Effect of oral aluminium hydroxide on iron absorption from iron(III)-hydroxide polymaltose complex in patients with iron deficiency anemia / a single-centre randomized controlled isotope study.

The study was carried out as an open-label, laboratory-blind, single-dose, randomized, two-period crossover, isotope efficacy study. Twenty-two patients with iron-deficiency anemia were enrolled in the study. The study consisted of two treatment phases of 15 days each, including blood sample measurements for Fe-59 activity. The 2 treatments were given orally. Treatment A was Fe-59 labeled iron(III)-hydroxide polymaltose complex (IPC, Maltofer), equivalent to 100 mg elemental iron given orally, and Treatment B consisted of Treatment A combined with 600 mg aluminium hydroxide (CAS 21645-51-2) (10 ml). No differences between the two treatment groups with regard to the erythrocyte uptake were found, and thus IPC can be used with aluminium hydroxide, if necessary.

Effect of oral tetracycline on iron absorption from iron(III)-hydroxide polymaltose complex in patients with iron deficiency anemia / a single-centre randomized controlled isotope study.

The study was carried out as an open-label, laboratory-blind, single-dose, randomized, two-period crossover, isotope efficacy study. Twenty-two patients with iron-deficiency anemia were enrolled in the study. The study consisted of two treatment phases of 15 days each, including blood sample measurements for Fe-59 activity. The two treatments were given orally. Treatment A was Fe-59 labeled iron(III)-hydroxide polymaltose complex (IPC, Maltofer) equivalent to 100 mg elemental iron given orally. Treatment B consisted of Fe-59 labeled IPC complex equivalent to 100 mg elemental iron and 500 mg tetracycline HCl (CAS 64-75-5) given orally. No differences between the two treatment groups with regard to the erythrocyte iron uptake were found, and thus IPC can be used with tetracycline, if necessary.

Effect of oral supplementation with iron(III)-hydroxide polymaltose complex on the immunological profile of adolescents with varying iron status.

OBJECTIVE: To assess the effects of iron supplementation on immunological parameters of adolescents with varying iron status. METHOD: Adolescents of both sexes with varying iron status were allocated to four treatment groups by using inclusion criteria. Three of the four groups received iron(III)-hydroxide polymaltose complex (IPC, Maltofer) containing 100 mg of iron 6 days a week for 8 months. The fourth group was given a placebo. Immunological parameters were assessed at baseline and after 4 and 8 months of supplementation. RESULTS: Increases from baseline to 4 months and from 4 to 8 months of supplementation were observed for Bactericidal Capacity of Neutrophils (BCA), NitroBlue Tetrazolium Reduction Test (NBT), and phytohaemagglutinin (PHA) in all three supplemented groups. No increase was found in the control placebo group except for PHA. No side effects were noted in any participants. CONCLUSION: IPC supplementation for eight months led to significant improvements of immunological parameters in iron deficient adolescents with and without anemia.

Safety and efficacy of iron(III)-hydroxide polymaltose complex / a review of over 25 years experience.

The following review of iron(III)-hydroxide polymaltose complex (IPC, Maltofer) shows that iron is significantly bioavailable after oral administration, especially in iron-deficient subjects. Numerous clinical trials in men, women, children and infants have shown that IPC is effective in treating iron deficiency anaemia (IDA). Due to its kinetic properties, IPC is best given with meals, and probably in an iron dose slightly higher than that of the classical iron salts. In terms of acceptance and patient compliance, IPC presents a clear advantage over ferrous salts. Many studies have shown a lower rate of treatment interruption with IPC than with ferrous salts. This is usually associated with a lower incidence of adverse events related to the upper gastro intestinal tract.

Milk iron content in breast-feeding mothers after administration of intravenous iron sucrose complex.

OBJECTIVE: To study the transfer of parenteral iron sucrose into maternal milk in the postpartum period. STUDY DESIGN: Ten healthy lactating mothers with functional iron deficiency 2-3 days after delivery received 100 mg intravenous iron sucrose and were observed together with a control group (n=5) without iron treatment during four days. Milk samples were taken before the treatment and every day afterwards. RESULTS: Mean milk iron levels at baseline were 0.43 and 0.46 mg/kg in the treatment and control group and decreased until the end of observation in both groups by 0.11 mg/kg. No significant difference between the groups was found on any study day as well as in the mean change from baseline over all four days. CONCLUSION: We could not show transfer of iron-sucrose into maternal milk for the given dosage. Since parenteral iron sucrose is widely used in obstetrics, the results provide information about safety of parenteral iron sucrose in the lactation period. The findings are also in agreement with other reports on active biological mammary gland regulation of milk iron concentration.