Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/26—Iron; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to a dosage regimen of ST10 (ferric trimaltol) for the treatment of patients suffering from iron deficiency with or without anaemia.
• the invention further relates to the treatment of patients with iron deficiency anaemia (IDA) in inflammatory bowel disease (IBD).
• IDA iron deficiency anaemia
• IBD inflammatory bowel disease
• Iron deficiency anaemia is characterised by low levels of iron in the blood and can be due to insufficient dietary intake of iron, or loss of iron from internal bleeding caused by diseases of the gastrointestinal or urinary tract, for example inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Ulcerative colitis is a chronic inflammatory disease affecting the colon and anaemia is recognised as a serious complication and symptom of ulcerative colitis.
• Iron deficiency anaemia (IDA) in inflammatory bowel disease (IBD) is primarily caused by chronic blood loss from inflamed mucosa and/or iron malabsorption in both active and inactive stages of the disease (1).
• Iron deficiency without anaemia, has also been shown to have clinical consequences for patients and individuals. Iron is an important component of many intracellular processes and the effect of iron deficiency or iron deficiency correction has been reported in chronic heart failure, growth, behaviour and learning in children and cognition in the elderly. When iron deficiency remains untreated it can lead to iron deficiency anaemia.
• treatment for iron deficiency anaemia is in the form of ferrous iron (Fe 2+ ) salts, (e.g.
• ferrous sulphate dosed orally as 300mg tablets (60mg elemental iron) three to four times daily.
• the duodenum can maximally absorb only 10-20 mg of iron a day, greater than 90% of ingested iron is not absorbed, leading to symptomatic adverse events including toxicity at the gastrointestinal mucosa, abdominal pain, nausea, vomiting, constipation, diarrhoea and dark stools, all of which are dose related and lead to poor adherence with treatment.
• ferrous iron tablets become lodged in the upper gastrointestinal tract contact irritation may occur causing erosion or ulceration.
• treatment with ferrous iron is badly tolerated leading to poor compliance, particularly in patients suffering from IBD who already have significant damage to their gastrointestinal tract (3-4).
• treatment with ferrous iron preparations in such patients can often worsen their condition and lead to treatment of such patients with intravenous iron administration.
• ST10 also referred to as ferric trimaltol and ferric maltol is a chemically stable complex formed between ferric iron (Fe 3+ ) and maltol (3-hydroxy-2-methyl-4-pyrone) was developed as an alternative to oral ferrous products and has been shown to correct iron deficiency in subjects with a history of ferrous sulphate intolerance (5).
• ST10 makes iron available in the gastrointestinal tract, providing iron in a biologically labile form for uptake across the mucus layer and intestinal wall (5). Since the iron is stabilized in a chelated form it is less toxic; therefore together with its high bioavailability, lower doses of elemental iron are administered thereby improving toxicity and patient compliance.
• Harvey et al (6) reported single doses of 30mg ST10 twice daily in patients recruited from gastroenterology clinics, those presenting with active inflammatory disease were excluded from the study.
• the inventors have found that a combination of a particular dosage regimen and tablet formulation have led to surprising improvement in haemoglobin levels in patients suffering from iron deficiency with or without anaemia and in addition, from anaemia resulting from Crohn's disease or ulcerative colitis, which were previously intolerant to oral ferrous products. These results have been reported as clinically meaningful even after a short treatment period of four weeks and confirm that ST10 is an effective therapy for iron deficiency anaemia in IBD patients and may be administered safely over a twelve week period or longer with reduced side effects and improved compliance. In addition the inventors have observed fewer common side effects associated with ferrous iron treatment such as gut related side effects, reduction in blackened stools and compatibility with antacid treatments.
• STIO for use in the treatment or prevention of iron deficiency with or without anaemia wherein STIO is administered orally as a 30mg preparation on an empty stomach twice daily wherein said 30mg preparation comprises at least 60% of STIO.
• a method of treating a patient suffering from iron deficiency with or without anaemia comprising administering orally to the patient a 30mg STIO preparation on an empty stomach wherein said 30mg preparation comprises at least 60% of ST10.
• ST10 formulation comprising 231.5mg of ST10 and one or more other excipients wherein said ST10 formulation comprises at least 60% of ST10.
• Figure 1 shows a graph of mean serum concentration of total iron over 6 hours after administration of ST10 at doses of 30mg bid, 60mg bid, 90mg bid on day 1.
• Figure 2 shows a graph of mean serum concentration of total iron over 6 hours after administration of ST10 at doses of 30mg bid, 60mg bid, 90mg bid on day 8.
• Figure 3 shows a graph of mean serum values over 6 hours of transferrin saturation after administration of ST10 at doses of 30mg bid, 60mg bid, 90mg bid on day 1.
• Figure 4 shows a graph of mean serum values over 6 hours of transferrin saturation after administration of ST10 at doses of 30mg bid, 60mg bid, 90mg bid on day 8.
• Figure 5 shows a graph of serum concentration of soluble transferrin receptor over 4 hours after administration of ST10 at doses of 30mg bid, 60mg bid, 90mg bid on days 1-7 and a single dose of
• Figure 6 shows a graph of mean serum concentration of ferritin over 6 hours after administration of STIO at 30mg bid, 60mg bid, 90mg bid on days 1-7 and a single dose of 30mg bid, 60mg bid, 90mg on day 8.
• STIO for use in the treatment or prevention of iron deficiency with or without anaemia wherein STIO is administered orally as a 30mg preparation on an empty stomach twice daily wherein said 30mg preparation comprises at least 60% of STIO.
• STIO for use in the treatment or prevention of iron deficiency anaemia in inflammatory bowel disease wherein STIO is administered orally as a 30mg preparation on an empty stomach twice daily wherein said 30mg preparation comprises at least 60% of ST10.
• ferric trimaltol is also known as ferric trimaltol and ferric maltol is a chemically stable complex formed between ferric iron (Fe 3+ ) and maltol (3-hydroxy-2-methyl-4-pyrone) according to the chemical structure below.
• the molar ratio of iron to hydroxypyrone is 1:3
• ST10 may be administered as a 30mg dose, where 30mg refers to the amount of elemental iron in the dose.
• the amount of ST10 equivalent to 30mg of elemental iron (Fe 3+ ) is 231.5mg.
• the dose may comprise varying amounts of other excipients for example lactose monohydrate, sodium lauryl sulphate, crospovidone, colloidal silicon dioxide, colloidal silicon dioxide and magnesium stearate.
• excipients for example lactose monohydrate, sodium lauryl sulphate, crospovidone, colloidal silicon dioxide, colloidal silicon dioxide and magnesium stearate.
• the ST10 preparation may be comprised within a capsule or tablet and mixed with a
• ST10 may be combined with an oral, non-toxic, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, dicaicium phosphate, calcium sulfate, mannitol, sorbitol and microcrystailine cellulose.
• Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylceliulose, polyethylene glycol and waxes.
• Lubricants used in these dosage forms may include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, and talc.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, crosearme!!ose sodium, and sodium starch glycoiate.
• the 30mg ST10 preparation comprises:
• the 30mg ST10 preparation comprises:
• the percentage of ST10 is at least 60% of the combined weight of ST10 and excipients.
• the ST10 preparation may be comprised within a capsule.
• the capsule is a hard gelatin capsule.
• the inventors have found that by significantly reducing the amount of lactose monohydrate in the preparation it was possible to reduce the overall size of the capsule without compromising on efficacy and absorption of the ST10 active ingredient.
• the new capsule formulation is smaller and easier to administer thereby improving patient compliance and tolerability.
• the capsule size may vary to effectively contain ST10 and the excipients.
• the capsule size may be defined as a size 1 capsule and has a volume of approximately 0.5ml, a length of approximately 19.4mm and a diameter of approximately 6.91mm. Slight variations to these dimensions are included within the scope of the invention.
• 30mg ST10 preparation may be administered as an oral preparation for example as a tablet or capsule formulation. In one example the 30mg ST10 preparation is administered as a size 1 capsule.
• 30mg ST10 preparation may be administered orally daily or twice daily on two separate occasions during the waking hours provided that the capsule is taken on an empty stomach. This is to reduce the likelihood of ST10 forming precipitates with food elements.
• the ST10 dose is administered once before breakfast and once prior to sleep. Administration at these times of the day is known to improve patient compliance and reduces the risk of side effects attributed to excess iron. Dosing on an empty stomach allows for lower dosage of elemental iron and consequently improved tolerability and therefore provides a significant improvement in reduction of side effects and patient compliance. Ferrous iron in comparison has to be taken with food to mask the associated gastrointestinal symptoms and is therefore given in much larger daily doses.
• the ST10 dose is administered orally.
• the ST10 dose may be administered as a solid dosage form or as a liquid formulation.
• An example of a suitable liquid formulation is provided in GB1404390.5.
• 30mg STIO preparation may be administered once daily, or once every two, three, four, five, six or seven days.
• 30mg STIO preparation may administered in the range of lOmg to 120mg once daily or once every two, three, four, five, six or seven days.
• STIO treatment is amenable to ongoing long term or maintenance treatment since it allows clinicians to associate blackened stools with disease pathogenesis.
• STIO provides iron through the normal physiological route as it is swallowed and absorbed across the gut wall. Iron absorbed through STIO is therefore under normal physiological control and is down-regulated through fewer iron transporting proteins available at the enterocyte luminal surface in subjects who have normal levels of iron. In this way overload and toxicity of iron is not a potential risk for STIO unlike conventional ferrous treatments.
• the low risk of iron overload provides another advantage for long term maintenance treatment using STIO and provides another safety advantage in the event of an overdose. Iron treatments are commonly prescribed to women of child-bearing age and there exists a risk to paediatric safety in the event of an overdose. The risk is significantly reduced for STIO because the levels of elemental iron are much lower in comparison to ferrous products which if overdosed in children can result in death due to liver failure.
• 30mg STIO preparation may be administered for a period of four weeks, a period of three weeks or a period of two weeks until iron levels have increased to normal levels.
• 30mg STIO preparation may be administered for any period until iron levels have increased to normal levels.
• a 30mg ST10 dose may be administered from a period of up to 16 weeks, but can be administered for as long as needed.
• 30mg ST10 preparation may be administered indefinitely as a maintenance dose.
• ST10 is for use in the treatment or prevention of iron deficiency anaemia in inflammatory bowel disease wherein said ST10 is administered orally as a 30mg size 1 capsule on an empty stomach twice daily, once before breakfast and once prior to sleep for up to a twelve week period wherein the percentage of ST10 is at least 60% of the combined weight of ST10 and excipients.
• ST10 is for use in the treatment or prevention of iron deficiency with or without anaemia wherein said ST10 is administered orally as a 30mg size 1 capsule on an empty stomach twice daily, once before breakfast and once prior to sleep for up to a twelve week period wherein the percentage of ST10 is at least 60% of the combined weight of ST10 and excipients.
• ST10 is also amenable to combination therapies. For example it is known to combine iron supplements with hormonal contraception tablets to treat anaemia in child bearing women who suffer from menorrhagia. Such combinations carry a risk of non-compliance when combined with ferrous iron since the gastrointestinal side effects could lead to non-compliance and risk of pregnancy. ST10 may be safely combined with hormone contraceptive tablets since the observed side effects seen for ferrous iron are not observed.
• ST10 for use in the treatment or prevention of iron deficiency anaemia in women suffering from menorrhagia.
• ST10 may be administered in accordance with the any of the previous aspects described herein.
• ST10 may be administered at the same time as antacid treatment, for example compounds containing calcium, magnesium, and proton pump inhibitors (PPIs).
• PPIs proton pump inhibitors
• ST10 doses may also be administered in diseases or situations that result in reduced or lack of gastric acid production for example after gastrectomy, in old age or atrophic or autoimmune gastritis.
• ferrous tablets should not be taken with stomach pH raising medications as this reduces the bioavailability of iron from ferrous products.
• iron deficiency with or without anaemia relates to all diseases and conditions associated with iron deficiency and for which treatment with iron would be therapeutically beneficial. Such diseases are those which are recognised as having iron deficiency as a complication or symptom.
• Iron deficiency is also referred to as sideropenia or hypoferremia and results from a prolonged period of inadequate iron intake; this medical state is called Latent Iron deficiency (LID) or Iron-deficient Erythropoiesis (IDE).
• LID Latent Iron deficiency
• IDE Iron-deficient Erythropoiesis
• Iron deficiency can be apparent before iron deficiency anaemia and include but are not limited to fatigue, hair loss, twitches, irritability, dizziness, brittle or grooved nails, appetite disorders such as pica and pagophagia, impaired immune function, chronic heart failure, growth, behaviour and learning in children, cognition in the elderly and Plummer-Vinson syndrome (PVS).
• PVS Plummer-Vinson syndrome
• IBD inflammatory bowel diseases
• SCCAI Simple Clinical Colitis Activity Index
• CDAI Crohn's Disease Activity Index
• a subject may be characterised as having active inflammatory disease or acute chronic inflammation by having a Simple Clinical Colitis Activity Index (SCCAI) of up to 4 or a Crohn's Disease Activity Index (CDAI) of up to 220.
• SCCAI Simple Clinical Colitis Activity Index
• CDAI Crohn's Disease Activity Index
• Conditions associated with iron deficiency anaemia include, but are not limited to chronic kidney disease (CKD), Systemic Lupus (SLE), rheumatoid arthritis, haematological cancers (e.g. Hodgkin's disease), chronic bacterial infection (e.g. osteomyelitis), viral hepatitis, HIV, AIDS, diseases of the gastrointestinal tract for example inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis.
• CKD chronic kidney disease
• SLE Systemic Lupus
• rheumatoid arthritis haematological cancers
• haematological cancers e.g. Hodgkin's disease
• the 30mg STIO dose described herein is useful in the treatment of iron deficiency with or without anaemia, wherein the iron deficiency is a result of, or associated with active inflammatory disease or acute chronic inflammation.
• STIO for use in the treatment or prevention of active inflammatory disease or acute chronic inflammation wherein STIO is administered orally as a 30mg preparation twice daily.
• STIO for use in the treatment or prevention of iron deficiency with or without anaemia, wherein the iron deficiency is a result of, or associated with active inflammatory disease or acute chronic inflammation wherein STIO is administered orally as a 30mg dose twice daily wherein the percentage of STIO is at least 60% of the combined weight of ST10 and excipients.
• the presence of active inflammatory disease or acute chronic inflammation can be determined by a physician using known methods, for example the recognised UC and CD clinical disease activity scales (SCCAI and CDAI).
• SCCAI and CDAI recognised UC and CD clinical disease activity scales
• the 30mg ST10 dose described herein are useful in the treatment of chronic kidney disease (CKD).
• CKD chronic kidney disease
• One of the recognised symptoms of this condition is iron deficiency with and without anaemia and so the ST10 dosages described herein provide a safe, effective and manageable treatment for subjects who are already taking one or more other medications.
• the invention in another aspect relates to a method of treating a patient suffering from iron deficiency anaemia associated with inflammatory bowel disease, the method comprising administering orally to the patient a 30mg ST10 preparation on an empty stomach, wherein the percentage of ST10 is at least 60% of the combined weight of ST10 and excipients.
• a method of treating a patient suffering from iron deficiency with or without anaemia the method comprising administering orally to the patient a 30mg STIO preparation on an empty stomach, wherein the percentage of STIO is at least 60% of the combined weight of STIO and excipients.
• STIO has use in the treatment of diseases resulting in iron deficiency including but not limited to disease associated with the urinary tract and renal function.
• the invention in another aspect relates to a 30mg STIO formulation comprising 231.5mg STIO and one or more excipients wherein the percentage of STIO is at least 60% of the combined weight of ST10 and excipients.
• the 30mg ST10 formulation may comprise
• Adverse events recorded in the study were mainly gastrointestinal in nature and occurred in the ST10 treated group with placebo-like frequency (38% of ST10 treated subjects and 40% placebo treated subjects).
• Group 1 9 subjects received ST10, 30 mg twice daily for 7 days (days 1-7) plus a final 30mg dose on the morning of day 8.
• Group 2 8 subjects received ST10, 60 mg twice daily for 7 days (days 1-7) plus a final 60mg dose on the morning of day 8.
• Group 3 7 subjects received ST10, 90 mg twice daily for 7 days (days 1-7) plus a final 90mg dose on the morning of day 8.
• ST10 was administered (30 mg, 60 mg or 90 mg) and blood samples collected over the following 6 h for analysis. 60mg was administered as two 30mg capsules and 90mg was administered as three 30mg capsules, both as a single dose. Subjects continued dosing with ST10 on the evening of day 1 then every morning and evening for the next 6 days (Days 2 to 7).
• Serum concentrations of transferrin, total iron binding capacity (TIBC), ferritin and soluble transferrin receptor; and reticulocyte haemoglobin concentrations (CHr) in whole blood were measured by central laboratories using appropriately validated methods. These studies used transferrin saturation and total serum iron as measurements of iron uptake from the gut into the transport mechanisms. In addition serum ferritin was used as a measure of iron storage status at the end of the dosing period; all of these measurements are standard and well recognised.
• Total iron binding capacity remained fairly constant over time and between dose groups with a mean concentration of approximately 70 ⁇ /L and individual values ranged between 47 and 101 ⁇ /L.
• TSAT Transferrin and Transferrin saturation
• Transferrin binds iron reversibly in the plasma and transports it into the cell via binding to the transferrin receptor.
• An increased plasma transferrin level is an indicator of iron deficiency anaemia.
• Soluble transferrin receptor remained fairly constant over time and between dose groups, with a mean concentration of approximately 4 mg/L and individual values ranged between 1.8 mg/L and 9.3 mg/L . Soluble transferrin receptor concentration decreases in response to iron treatment.
• Figure 5 shows no difference between the 60mg and 90mg dose, however in comparison the concentration of sTFr is significantly higher for the 30mg dose, supporting the finding that doses of 30mg and above are well tolerated and effective.
• Mean ferritin concentrations remained fairly constant over the individual concentration time profiles, with higher ferritin serum concentrations on day 8 compared to day 1.
• Mean serum ferritin values for the 30 mg, 60 mg and 90 mg dose groups were around 15 ⁇ g/L, 10 ⁇ g/L and 13 ⁇ g/L on day 1 and 22 ⁇ g/L, 22 ⁇ g/L and 32 ⁇ g/L on day 8, respectively.
• Reticulocytes are immature red blood cells, formed in the bone marrow but also found in the circulating blood. They represent less than 5% of the red blood cell mass, but provide an early indicator of change in total haemoglobin
• reticulocytes or immature red blood cells are a marker for the presence of anaemia and so measurement of the levels of haemoglobin allows progression of treatment for anaemia to be monitored.
• Haemoglobin (Hb) content in reticulocytes seen over 8 days is evidence of the incorporation of iron into normal physiological functions and therefore translates to a clinical benefit associated with the dose administered.

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