Ferric Maltol: A New Oral Iron Formulation for the Treatment of Iron Deficiency in Adults.

OBJECTIVE: To review the pharmacology, efficacy, and safety of ferric maltol (FM), an oral iron formulation, for iron deficiency anemia (IDA). DATA SOURCES: A MEDLINE/PubMed and EMBASE (January 1, 1985, to June 19, 2020) literature search was performed using the terms ferric maltol, accrufer, feraccru, iron maltol, ferric trimaltol, iron deficiency, iron deficiency anemia, inflammatory bowel disease, and chronic kidney disease. Additional data sources included prescribing information, abstracts, and the National Institutes of Health Clinical Trials Registry. STUDY SELECTION/DATA EXTRACTION: English language literature evaluating FM pharmacology, pharmacokinetics, efficacy, or safety in the treatment of IDA were reviewed. DATA SYNTHESIS: FM is a ferric, non-salt-based oral iron formulation demonstrating improved tolerance in patients with previous intolerance to other iron formulations. Phase 3 trials demonstrated significant improvements in anemia and serum iron parameters in patients with inflammatory bowel disease (IBD) and chronic kidney disease (CKD). Common adverse effects were gastrointestinal intolerance. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: FM is an effective and well-tolerated alternative to oral iron salts for patients with IBD or CKD and IDA. Emerging data suggest that FM is noninferior to intravenous (IV) ferric carboxymaltose in patients with IBD and IDA. Prior to selecting FM over IV iron products, consideration should be given to time to normalization of Hb, ease of administration, cost, and tolerability. CONCLUSION: FM is a relatively safe, effective oral iron therapy that may be better tolerated than other oral iron formulations. FM may be an effective alternative to IV iron in patients with IBD.

Optimal EPO dosing in hemodialysis patients using a non-linear model predictive control approach.

Anemia management with erythropoiesis stimulating agents is a challenging task in hemodialysis patients since their response to treatment varies highly. In general, it is difficult to achieve and maintain the predefined hemoglobin (Hgb) target levels in clinical practice. The aim of this study is to develop a fully personalizable controller scheme to stabilize Hgb levels within a narrow target window while keeping drug doses low to mitigate side effects. First in-silico results of this framework are presented in this paper. Based on a model of erythropoiesis we formulate a non-linear model predictive control (NMPC) algorithm for the individualized optimization of epoetin alfa (EPO) doses. Previous to this work, model parameters were estimated for individual patients using clinical data. The optimal control problem is formulated for a continuous drug administration. This is currently a hypothetical form of drug administration for EPO as it would require a programmable EPO pump similar to insulin pumps used to treat patients with diabetes mellitus. In each step of the NMPC method the open-loop problem is solved with a projected quasi-Newton method. The controller is successfully tested in-silico on several patient parameter sets. An appropriate control is feasible in the tested patients under the assumption that the controlled quantity is measured regularly and that continuous EPO administration is adjusted on a daily, weekly or monthly basis. Further, the controller satisfactorily handles the following challenging problems in simulations: bleedings, missed administrations and dosing errors.

Evaluation of iron stores in hemodialysis patients on maintenance ferric Carboxymaltose dosing.

BACKGROUND: Iron is administered intravenously (IV) to many dialysis patients at regular intervals and iron stores are evaluated through periodic measurements of ferritin and transferrin saturation (TSAT). In patients without kidney diseases, large single doses of IV iron lead to a transient rise in serum ferritin that does not reflect iron stores. It is not known whether and to what extent smaller IV iron doses used to maintain adequate stores in hemodialysis patients lead to transient spurious elevations of ferritin and TSAT. METHODS: Ferritin and TSAT were serially determined over four weeks after the administration of ferric carboxymaltose (FCM) in hemodialysis patients on a stable maintenance FCM dosing regimen of 100 mg or 200 mg every four weeks. RESULTS: Ferritin values increased by 113 ± 72.2 µg/l (P < 0.001) from baseline to the peak value and remained significantly elevated until two weeks after the administration of 100 mg FCM (n = 19). After the administration of 200 mg FCM (n = 12), ferritin values increased by 188.5 ± 67.56 µg/l (P < 0.001) and remained significantly elevated by the end of week three. TSAT values increased by 12.0 ± 9.7% (P < 0.001) and 23.1 ± 20.4% (P = 0.002) in patients receiving 100 or 200 mg FCM, respectively, and returned to baseline within four days. CONCLUSIONS: IV administration of FCM at doses of 100 or 200 mg in hemodialysis patients leads to dose-dependent transient ferritin elevations of extended duration. Temporal coordination of blood sampling for iron status evaluation with the maintenance IV iron dosing schedule is advisable. TRIAL REGISTRATION: ISRCTN12825165 (retrospectively registered 01/02/2019).

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

The Use of Magnetic Resonance Imaging for Non-Invasive Assessment of Venofer® Biodistribution in Rats.

PURPOSE: The aim of this study was to determine the potential of magnetic resonance imaging to evaluate the biodistribution of exogenous iron within 24 h after one single injection of Venofer® (iron sucrose). METHODS: Venofer® was evaluated in vitro for its ability to generate contrast in MR images. Subsequently, iron disposition was assessed in rats with MRI, in vivo up to 3 h and post mortem at 24 h after injection of Venofer®, at doses of 10- and 40 mg/kg body weight (n = 2 × 4), or saline (n = 4). RESULTS: Within 10-20 min after injection of Venofer®, transverse relaxation rates (R2) clearly increased, representative of a local increase in iron concentration, in liver, spleen and kidney, including the kidney medulla and cortex. In liver and spleen R2 values remained elevated up to 3 h post injection, while the initial R2 increase in the kidney was followed by gradual decrease towards baseline levels. Bone marrow and muscle tissue did not show significant increases in R2 values. Whole-body post mortem MRI showed most prominent iron accumulation in the liver and spleen at 24 h post injection, which corroborated the in vivo results. CONCLUSIONS: MR imaging is a powerful imaging modality for non-invasive assessment of iron distribution in organs. It is recommended to use this whole-body imaging approach complementary to other techniques that allow quantification of iron disposition at a (sub)cellular level.

Pharmacokinetics of ferric pyrophosphate citrate administered via dialysate and intravenously to pediatric patients on chronic hemodialysis.

BACKGROUND: Iron deficiency is a common cause of anemia in pediatric patients with hemodialysis-dependent chronic kidney disease (CKD-5HD). Ferric pyrophosphate citrate (FPC, Triferic®) donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Administration of FPC via dialysate or intravenously (IV) may provide a suitable therapeutic option to current IV iron preparations for these patients. METHODS: The pharmacokinetics and safety of FPC administered via dialysate and IV to patients aged < 6 years (n = 3), 6 to < 12 years (n = 4), and 12 to <18 years (n = 15) were investigated in a multicenter, open-label, two-period, single-dose study. FPC (0.07 mg iron/kg) was infused IV into the venous blood return line during hemodialysis session no. 1. FPC iron was added to bicarbonate concentrate to deliver 2 µM (110 µg/L) iron via dialysate during hemodialysis session no. 2. RESULTS: Mean serum total iron concentrations peaked 3 to 4 h after administration via dialysate and 2 to 4 h after IV administration and returned to baseline by 10 h after the start of hemodialysis for both routes. Iron exposure was greater after administration via dialysate than after IV administration. The absolute amount of absorbed iron after administration via dialysate roughly doubled with increasing age, but the weight-normalized amount of absorbed iron was relatively constant across age groups (~ 0.06-0.10 mg/kg). FPC was well tolerated in the small number of patients studied. CONCLUSIONS: FPC iron can be administered to pediatric patients with CKD-5HD via dialysate or by the IV route. Further study of FPC administered to maintain hemoglobin concentration is indicated.

Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia.

Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIFα in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.

Effective use of modeling and simulation in designing bioequivalence and comparability studies of large-molecule compounds: the case of erythropoietin.

OBJECTIVE: Bioequivalence and comparability studies are necessary for changing formulations of large-molecule drugs, such as antibody drugs and protein products, and in the development of their biosimilars. This study is the first application of modeling and simulation (M&S) in the design of bioequivalence and comparability studies of erythropoietin as an example of a large-molecule drug. METHODS: A novel population pharmacokinetic and pharmacodynamic (PPK/PD) model was developed for erythropoietin. Based on this PPK/PD model, the probabilities of success of bioequivalence and comparability studies were simulated with various numbers of subjects and samples. RESULTS: The simulation indicated that the minimum numbers of subjects and samples required to satisfy the criteria for bioequivalence and comparability studies were as follows: fewest for the area under the serum concentration-time curve, more for the area under the efficacy-time curve, and most for the maximum serum concentration of erythropoietin. CONCLUSION: These results suggested that M&S could be successfully applied in the design of bioequivalence and comparability studies of large-molecule drugs.

Update on intravenous iron choices.

PURPOSE OF REVIEW: Iron deficiency is a major factor in the prevalence and severity of anemia in patients with chronic kidney disease (CKD). We review the pathophysiology impairing normal intestinal iron absorption in CKD and compare the characteristics of newer intravenous (i.v.) iron agents to the longstanding i.v. iron products in the market. RECENT FINDINGS: The newer iron products, ferumoxytol, ferric carboxymaltose, and iron isomaltoside, more avidly bind iron, minimizing the release of labile iron during infusions, thus permitting large dose infusions. These irons also have more complex carbohydrate shells than their predecessors, which may also diminish reactions. Newer agents can be routinely administered at higher single doses, in as little as 15 min, with an acceptable safety profile. SUMMARY: Newer i.v. iron products permit the rapid, and sometimes complete, repletion of iron-deficient patients with a single dose. However, further studies examining the long-term risks and benefits of i.v. iron repletion are needed.

Pharmacokinetics of darbepoetin alfa after single, intravenous or subcutaneous administration in Japanese pediatric patients with chronic kidney disease.

BACKGROUND: Darbepoetin alfa (DA) is beneficial for pediatric patients for its less injection frequency and greater maximum dose compared to recombinant human erythropoietin. Here, we evaluated pharmacokinetics of DA in Japanese pediatric patients with chronic kidney disease (CKD). METHODS: CKD patients (2-18 years old, n = 8 each) received a single dose of body weight adjusted DA either intravenously or subcutaneously. RESULTS: When administered intravenously, the area under the concentration-time curve from time zero to infinity (AUC0-∞), clearance (CL) and terminal half-life (t 1/2) of DA were 263.7 ng · h/mL, 1.77 mL/h/kg and 26.25 h, respectively (mean). In patients under 12 years old, AUC0-∞, CL and t 1/2 were 219.1 ng · h/mL, 2.19 mL/h/kg, 23.62 h, respectively. These values were mostly similar to those of Japanese adult CKD patients, though AUC0-∞ tended to be lower and CL tended to be higher in the subjects under 12 years old. When administered subcutaneously, time to reach maximum concentration (t max) and maximum concentration (C max) were 24.47 h and 1.704 ng/mL, and AUC0-∞, apparent clearance (CL/F) and t 1/2 were 141.1 ng · h/mL, 3.23 mL/h/kg and 46.73 h, respectively. In patients under 12 years old, t max and C max were 7.50 h and 2.053 ng/mL, and AUC0-∞, CL/F and t 1/2 were 136.7 ng · h/mL, 3.29 mL/h/kg and 37.75 h, respectively, which was higher in C max, faster in t max and shorter t 1/2 compared to adult CKD patients, while AUC was not obviously different. CONCLUSION: The pharmacokinetics of DA in pediatric CKD patients is not obviously different from those in adult.

Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration.

Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine.

A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

2,2-Dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/ß(0) thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. .

A predictive algorithm for the management of anaemia in haemodialysis patients based on ESA pharmacodynamics: better results for less work.

BACKGROUND: Many anaemia management algorithms recommend changes to erythropoiesis-stimulating agent (ESA) doses based on frequent measurement of haemoglobin levels in keeping with the ESA datasheets. We designed a predictive anaemia algorithm based on ESA pharmacodynamics, which we hoped would improve compliance with haemoglobin targets and reduce workload. METHODS: A new algorithm was designed which predicted the 3-month steady-state haemoglobin concentration following a change in ESA dose and only recommended a change if it was outside the range 10.5-12.5 g/dL. Data were collected prospectively for 3 months prior and 15 months subsequent to implementing the algorithm. RESULTS: A total of 214 prevalent dialysis patients were included in the audit. After 12 months, the haemoglobin concentration was 11.4 g/dL, near the midpoint of the target range, with a narrowing of the distribution (SD 1.46 to 1.25 g/dL, P < 0.0001). The proportion of patients with a haemoglobin level in the target range increased from 56% to 66% (P < 0.001) principally due to a reduction in the number of patients with high haemoglobin levels. There was no significant change in the ESA dose over the audit period. The number of prescription changes fell from 1/2.5 months to 1/6.1 months after 12 months (P < 0.001). CONCLUSIONS: Switching prevalent haemodialysis patients to a predictive anaemia management algorithm improved compliance with haemoglobin targets, reduced the number of patients with high haemoglobin levels and reduced the number of ESA dose changes required.

A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease.

Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α(2) γ(2) ) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/ß thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease.

Erythropoietin-coated ZP-microneedle transdermal system: preclinical formulation, stability, and delivery.

PURPOSE: To evaluate the feasibility of coating formulated recombinant human erythropoietin alfa (EPO) on a titanium microneedle transdermal delivery system, ZP-EPO, and assess preclinical patch delivery performance. METHODS: Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. EPO liquid formulation was coated onto titanium microneedles by dip-coating and drying. Stability of coated EPO was assessed by SEC-HPLC, CZE and potency assay. Preclinical in vivo delivery and pharmacokinetic studies were conducted in rats with EPO-coated microneedle patches and compared to subcutaneous EPO injection. RESULTS: Studies demonstrated successful EPO formulation development and coating on microneedle arrays. ZP-EPO patch was stable at 25°C for at least 3 months with no significant change in % aggregates, isoforms, or potency. Preclinical studies in rats showed the ZP-EPO microneedle patches, coated with 750 IU to 22,000 IU, delivered with high efficiency (75-90%) with a linear dose response. PK profile was similar to subcutaneous injection of commercial EPO. CONCLUSIONS: Results suggest transdermal microneedle patch delivery of EPO is feasible and may offer an efficient, dose-adjustable, patient-friendly alternative to current intravenous or subcutaneous routes of administration.

Absorption, distribution, metabolism and excretion of peginesatide, a novel erythropoiesis-stimulating agent, in rats.

The pharmacokinetics (PK) (absorption, distribution, metabolism, excretion) of peginesatide, a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent (ESA), was evaluated in rats. The PK profile was evaluated at 0.1-5 mg·kg(-1) IV using unlabeled or [(14)C]-labeled peginesatide. Mass balance, tissue distribution and metabolism were evaluated following IV administration of 5 mg·kg(-1) [(14)C]-peginesatide, with tissue distribution also evaluated by quantitative whole-body autoradiography (QWBA) following an IV dose of 17 mg·kg(-1) [(14)C]-peginesatide. Plasma clearance was slow and elimination was biphasic with unchanged peginesatide representing >90% of the total radioactivity of the total radioactive exposure. Slow uptake of the radiolabeled compound from the vascular compartment into the tissues was observed. Biodistribution to bone marrow and extramedullary hematopoietic sites, and to highly vascularized lymphatic and excretory tissues occurred. A predominant degradation event to occur in vivo was the loss of one PEG chain from the branched PEG moiety to generate mono-PEG. Renal excretion was the primary mechanism (41%) of elimination, with parent molecule (67%) the major moiety excreted. In conclusion, elimination of [(14)C]-peginesatide-derived radioactivity was extended, retention preferentially occurred at sites of erythropoiesis (bone marrow), and urinary excretion was the primary elimination route.

Equivalent effects on fecal reactive oxygen species generation with oral supplementation of three iron compounds: ferrous sulfate, sodium iron EDTA and iron polymaltose.

BACKGROUND: In any context of iron supplementation in the prenatal prophylaxis or therapeutic dosage range, a large amount will remain unabsorbed and pass through the intestinal tract into the colonic digesta possibly causing increased oxidation. AIM: To compare the generation of fecal reactive oxygen species (ROS) in situ after daily consumption of 100 mg of elemental iron in three frequently used forms of iron supplements. METHODS: Ten healthy, iron-repleted adult males were investigated before and during supplementation with three oral iron compounds: 100 mg of oral iron were given as ferrous sulfate, Na Fe-EDTA and iron polymaltose for 6 days to each subject in an individually stratified sequence. Stool samples were collected and analyzed for iron content and the in situ generation of fecal ROS. RESULTS: Significant increases in fecal ROS generation were observed during oral iron supplementation. No statistical differences were seen in either residual concentrations of non-heme iron in stool or the level of fecal ROS generation between the three Fe compounds. There was, however, a significant association between the iron concentration in the stool and ROS generation. CONCLUSION: In spite of the differences in their chemical characteristics, none of the three distinct iron complexes reduced oxidative stress in the intestinal lumen.

Impact of oral iron challenges on circulating non-transferrin-bound iron in healthy Guatemalan males.

INTRODUCTION: Oral iron as a supplement has been associated with adverse health consequences, especially in the context of young children with active malaria. A potential aggravating role of non-transferrin-bound iron (NTBI) has been proposed. MATERIAL AND METHODS: NTBI responses in both a fasting and post-oral iron dosing situation were related to serum iron concentration and ferritin status. Fasting and 1, 2, and 3 h postdose serum samples were obtained in conjunction with oral ferrous sulfate supplementation in aqueous solution of 0, 15, 30, 60, 120 and 240 mg Fe in a cohort of 8 healthy Guatemalan men over a 9-week metabolic protocol. Hemoglobin, serum ferritin, percent transferrin saturation, serum iron and NTBI were all measured. RESULTS: Circulating levels of serum iron and NTBI increased in a graded fashion in response to oral iron, with the relative increment for NTBI slightly greater than that of iron. Detectable NTBI was occasionally measured in fasting specimens, more frequently in subjects with high ferritin status. Post-iron NTBI responses, by contrast, were higher in normal-ferritin subjects in absolute terms, and rose with increasing postabsorptive serum iron responses. DISCUSSION: The appearance and response of circulating NTBI were consistent with recognized principles of iron regulation.

Erythropoiesis-stimulating agents for the management of anemia of chronic kidney disease: past advancements and current innovations.

Over the last century, remarkable advances have been made in the care of patients with end stage renal disease (ESRD), resulting in improved prognosis. However, for decades after the advent of dialysis, anemia-associated symptoms continued to adversely affect patients' daily lives. The identification, isolation, and eventual cloning of erythropoietin and its receptor led to development of erythropoiesis stimulating agents, revolutionizing anemia management. Continued advancements have paved the way for the discovery of novel erythropoiesis stimulating agents with enhanced properties. This article charts the history of anemia management in patients with ESRD, including the discovery of erythropoietin, and briefly reviews the development, mechanism of action, and select attributes of erythropoiesis-stimulating agents.

Erythropoiesis-stimulating agents in renal medicine.

The four currently available erythropoiesis-stimulating agents (ESAs), the main drugs for correcting anemia in patients with chronic kidney disease (CKD), are epoetin alfa, epoetin beta, darbepoetin alfa, and continuous erythropoietin receptor activator. The last two have much longer half-lives, which means they can be administered less frequently. The expiry of the patents for epoetin alfa and epoetin beta some years ago opened up the way for the production of a number of biosimilars that are now marketed in the European Union. Because biosimilars cannot be identical to their originator, a complex and still-evolving regulatory policy has been generated, but there are still a number of issues concerning international naming, automatic substitution, and safety. All ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. Following the publication of a number of trials indicating no benefit (and even possible harm) when ESAs are used to aim at near-normal hemoglobin levels in CKD patients, the hemoglobin target has become a major subject of discussion. According to the position statement of the Anemia Group of the European Renal Best Practice, it should generally be about 11-12 g/dL; however, a risk-benefit evaluation is warranted in individual patients, and high ESA doses driven by hyporesponsiveness should be avoided.