WO2017120311A1 - Composition therapy with an iron compound and a citrate compound - Google Patents

Composition therapy with an iron compound and a citrate compound

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Publication number
WO2017120311A1
WO2017120311A1 PCT/US2017/012300 US2017012300W WO2017120311A1 WO 2017120311 A1 WO2017120311 A1 WO 2017120311A1 US 2017012300 W US2017012300 W US 2017012300W WO 2017120311 A1 WO2017120311 A1 WO 2017120311A1
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iron
compound
citrate
mg
solution
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PCT/US2017/012300
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French (fr)
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Ajay Gupta
Gary BRITTENHAM
Raymond Pratt
Vivian H. LIN
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Rockwell Medical, Inc.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/26Iron; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/194Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Abstract

Combination therapy comprising an iron compound, preferably soluble ferric pyrophosphate (SFP), in combination with a citrate compound is disclosed. Methods of using the combination therapy in the treatment of iron deficiency, with or without anemia, including iron-refractory iron deficiency anemia and other iron-sequestration syndromes, and pharmaceutical compositions and kits comprising SFP or another iron compound and a citrate compound are also disclosed.

Description

COMBINATION THERAPY WITH AN IRON COMPOUND AND A CITRATE

COMPOUND

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62/275,487 filed January 6, 2017, and U.S. Provisional Patent Application No. 62/432,564, filed December 9, 2016, is hereby claimed, and the disclosures thereof are incorporated herein by reference.

FIELD OF INVENTION

[0002] The present disclosure relates to combination therapy comprising an iron compound and a citrate compound for use in treating iron deficiency.

BACKGROUND

[0003] Iron deficiency is the most common micronutrient deficiency in the world. In absolute iron deficiency, iron stores are absent, and total body iron is decreased. In functional iron deficiency, iron stores are present, but the supply of iron to plasma transferrin is inadequate, e.g., due to administration of erythropoiesis- stimulating agents that increase the iron requirements above the amounts that can be mobilized from these stores. Iron is required for several vital physiological functions, including: (1) oxygen transport and utilization, e.g., as a carrier of oxygen from lung to tissues; (2) energy production; (3) cellular proliferation; (4) transport of electrons within cells; (5) as a co-factor of essential heme and non-heme enzymatic reactions in neurotransmission, synthesis of steroid hormones, synthesis of bile salts, and detoxification processes in the liver; and (6) destruction of pathogens.

Severe iron deficiency, i.e., iron deficiency anemia, is therefore particularly debilitating. Among the consequences of iron deficiency anemia are increased maternal and fetal mortality, an increased risk of premature delivery and low birth weight, learning disabilities and delayed psychomotor development, impaired neurocognitive development in infancy and childhood that may be irreversible, reduced work capacity, impaired immunity (increased risk of infection), an inability to maintain body temperature, and an associated/increased risk of lead poisoning. It is well-known that it is very difficult to treat an iron deficiency with orally administered iron supplements. In general, relatively large doses are needed to achieve a desired therapeutic effect, and oral administration of iron supplements is known to be commonly accompanied by undesirable side effects including nausea, epigastric pain, vomiting, constipation and gastric irritation. [0004] One type of iron-deficiency anemia known as iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal-recessive disorder. IRIDA is characterized by iron deficiency anemia unresponsive to oral iron therapy and a delayed, incomplete response to parenteral iron treatment (De Falco et al. Haematologica 2013; 98: 845-853; Finberg et al. Nat Genet 2008; 40: 569-571; Heeney MM and Finberg KE. Hematol Oncol Clin North Am 2014; 28: 637-52). IRIDA patients have a congenital microcytic, hypochromic anemia, low plasma iron and transferrin saturation, and a normal or decreased serum ferritin

concentration. The mutations responsible are in the gene TMPRSS6, which encodes matriptase-2 (MT-2), a type II plasma membrane serine protease that cleaves hemojuvelin to negatively regulate hepcidin, the systemic iron-regulatory protein (Finberg et al., supra; Du et al. Science 2008; 320: 1088-1092; Wang et al. Front Pharmacol 2014; 5: 114). Hepcidin acts by binding to and inactivating the iron-export protein, ferroportin, preventing the efflux of iron from enterocytes, macrophages, and hepatocytes into plasma for transport by transferrin to the erythroid marrow and other tissues (Ganz T. Physiol Rev 2013; 93: 1721-1741). The TMPRSS6 gene mutations result in inappropriately high plasma hepcidin concentrations, leading to iron sequestration resulting from obstruction of both iron absorption by enterocytes and iron release from macrophages and hepatocytes. Much more common are other disorders that result in elevated concentrations of plasma hepcidin that restrict the supply of iron to the erythroid marrow and other iron-requiring tissues (Goodnough et al. Blood 2013; 116: 4754- 4761). In iron- sequestration syndromes, body iron stores are adequate or even increased, but cannot be utilized to meet physiological iron requirements because increases in plasma hepcidin prevent enterocytes, macrophages, and hepatocytes from supplying sufficient iron to transferrin. With both iron sequestration and functional iron deficiency, the supply of iron to plasma transferrin is inadequate to meet the needs of the erythroid marrow and other iron- requiring tissues. Other diseases associated with sustained abnormally high hepcidin levels and iron sequestration include chronic inflammatory conditions, chronic kidney disease, autoimmune diseases, chronic infections, bacterial, viral and fungal infections, rheumatologic diseases, inflammatory bowel disease, critical illness, a variety of other chronic diseases, and cancer (e.g., malignancies).

[0005] Currently available parenteral iron preparations are iron-carbohydrate complexes that must first be taken up and processed by reticuloendothelial macrophages to free the iron from the carbohydrate for subsequent export via ferroportin. Consequently, parenteral iron treatment is unable to circumvent a hepcidin-induced block in iron export and produces only a sluggish, partial correction of microcytic anemia. Patients having iron deficiency (absolute and functional), iron sequestration syndrome, anemia and/or elevated hepcidin levels, including IRIDA and chronic inflammatory conditions, are in need of improved iron therapy options.

[0006] A variety of iron salts and other therapeutic iron compounds have been used for the treatment of iron deficiency, including ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous succinate, ferric hydroxide, ferric citrate, ferric maltol, and iron polysaccharide complex. Soluble ferric pyrophosphate (SFP) is a class of iron salts which comprise a mixture of iron chelated or coordinated to citrate and pyrophosphate and includes ferric pyrophosphate citrate (FPC, TRIFERIC, Rockwell Medical, Inc., Wixom, Michigan) that has a molecular mass of about 1000 Da and is highly soluble in aqueous solutions. The administration of SFP overcomes both absolute and functional iron deficiencies and iron- sequestration syndromes in many patients. Upon parenteral administration, SFP-iron directly binds to apo-transferrin, thereby delivering SFP-iron to bone marrow directly, bypassing the reticuloendothelial system (Gupta et al. J Am Soc Nephrol 2010; 21: 429A; Pratt et al., / Clin Pharmacol 2016; DOI: 10.1002/jcph.819). U.S. Patent Nos. 6,689,275; 6,779,468; and 7,857,977; incorporated herein by reference, disclose the addition of SFP to liquid bicarbonate solutions for hemodialysis. U.S. Provisional Patent No. 62/214,908, incorporated herein by reference, discloses a solid particulate formulation of SFP.

SUMMARY OF INVENTION

[0007] The present disclosure is directed to combination therapy comprising an iron compound and a citrate compound. In one aspect, the disclosure provides pharmaceutical compositions comprising an iron compound and a citrate compound, optionally compositions for oral administration. In one aspect, the pharmaceutical composition comprises an iron compound in an amount of about 0.2 mg iron to about 5 mg iron per kg bodyweight of a subject, for example, about 5 mg iron to about 500 mg iron. In another aspect, the pharmaceutical formulation comprises a citrate compound in an amount of about 0.5 mmol to about 2 mmol per kg bodyweight of a subject, for example, about 0.5 mmol to about 100 mmol.

[0008] The disclosure also provides kits comprising an iron compound and a citrate compound and instructions for co-administering a therapeutically effective amount of the iron compound and the citrate compound to a subject having iron deficiency, with or without anemia. In one aspect, the kit comprises an iron compound in an ampule containing about 5.44 mg/niL Fe in water. In another aspect, the kit comprises a citrate compound comprising citric acid and sodium citrate, for example, about 128 mg/mL citric acid and about 98 mg/mL sodium citrate. Optionally, the kit comprises a citrate compound that is a solution comprising about 640 mg/5 mL citric acid and about 490 mg/5 mL hydrous sodium citrate in water, e.g., Shohl's solution. In one aspect, the iron compound and/or citrate compound is in a pharmaceutical composition for oral administration.

[0009] The present disclosure provides methods and medical uses for treating iron deficiency, with or without anemia, in a subject in need thereof. In one aspect, a method of treating iron deficiency comprises co-administering a therapeutically effective amount of an iron compound and a citrate compound to a subject in need thereof. In another aspect, the present disclosure provides an iron compound and a citrate compound for use in treating iron deficiency. In still another aspect, the present disclosure provides use of an iron compound and a citrate compound in the manufacture of a medicament for treating iron deficiency. In another aspect, a method of increasing serum iron comprises co-administering a

therapeutically effective amount of an iron compound and a citrate compound to a subject in need thereof, optionally in an amount effective to increase serum iron by at least 100 μg/dL compared to baseline. In still another aspect, a method of increasing hemoglobin levels comprising co-administering a therapeutically effective amount of an iron compound and a citrate compound to a subject in need thereof, optionally in an amount effective to increase hemoglobin concentration by at least 1 g/dL compared to baseline. In any of the foregoing methods, the iron compound and citrate compound may be administered concurrently, e.g., in an admixture, or one component (for example, the citrate compound) may be administered first, followed by administration of the second component, optionally within a period of 15 minutes or less. In one aspect, the iron compound is administered first. In another aspect, the citrate compound is administered first. Optionally, the iron compound and/or citrate compound is administered orally, for example, both the iron compound and citrate compound are administered orally. In various aspects, the iron compound and/or citrate compound is administered one, two, or three times per day. Optionally, the iron compound and/or citrate compound is administered at least one hour before or two hours after a meal.

[0010] In any of the foregoing methods, the iron compound and citrate compound may be co-administered to a subject in need thereof in an amount effective to improve at least one serum iron pharmacokinetic parameter compared to an equivalent dosage of the iron compound administered without the citrate compound. In various aspects, co-administering an iron compound and a citrate compound to a subject increases the maximum serum iron concentration in a dose interval (Cmax), increases the bioavailability of the iron compound, and/or increases the amount of iron absorbed from the iron compound, compared to an equivalent dosage of the iron compound administered without the citrate compound.

[0011] In any of the pharmaceutical compositions, kits, methods, and medical uses of the present disclosure, the iron compound is optionally selected from ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous succinate, ferric citrate, ferric pyrophosphate, SFP, ferric hydroxide, ferric pyrophosphate citrate, iron polymaltose, iron ascorbate, ferric (tri)maltol, heme iron polypeptide, iron EDTA, iron polysaccharide complex, and combinations thereof. The iron compound optionally comprises iron in an amount from 7% to 11% by weight, citrate in an amount from 14% to 30% by weight, pyrophosphate in an amount from 10% to 20% by weight, and phosphate in an amount of 2% or less by weight. The iron compound may be administered at a dosage of about 0.2 mg iron to about 5 mg iron per kg bodyweight, for example, about 3 mg Fe per kg bodyweight. The citrate compound is optionally selected from the group consisting of citric acid, sodium citrate, potassium citrate, calcium citrate, magnesium citrate, ammonium citrate, combinations of any of the foregoing, and solutions thereof. In one aspect, the citrate compound comprises citric acid and sodium citrate, e.g., in an aqueous solution such as Shohl's solution. The citrate compound may be administered at a dosage of about 0.5 mmol to about 2 mmol per kg bodyweight, for example, about 0.67 mmol per kg.

[0012] The pharmaceutical formulations, kits, and methods described herein are used to treat subjects in need. Suitable subjects include patients having iron deficiency (absolute and functional) or iron-sequestration syndrome(s), with or without anemia, including IRIDA, renal anemia, anemia of chronic disease, anemia of chronic inflammation, anemia with autoimmune and rheumatologic diseases, anemia with inflammatory bowel disease, anemia with bacterial, viral and fungal infections, cancer-related anemia, chemotherapy-related anemia, anemia caused by impaired production of ESA with ESA treatment, hypochromic anemia, anemia of inflammation, and microcytic anemia. Suitable subjects also include those exhibiting elevated serum and/or urinary hepcidin levels caused by conditions such as IRIDA, inflammatory conditions, chronic kidney disease, autoimmune diseases, chronic infections, bacterial, viral and fungal infections, critical illness, rheumatologic diseases, inflammatory bowel disease, a variety of other chronic diseases or other conditions with hypoferremia (decreased serum iron and transferrin saturation), and cancer (e.g., malignancies).

[0013] The foregoing summary is not intended to define every aspect of the invention, and other features and advantages of the present disclosure will become apparent from the following detailed description, including the drawings. The present disclosure is intended to be related as a unified document, and it should be understood that all combinations of features described herein are contemplated, even if the combination of features are not found together in the same sentence, paragraph, or section of this disclosure. In addition, the disclosure includes, as an additional aspect, all embodiments of the invention narrower in scope in any way than the variations specifically mentioned above. With respect to aspects of the disclosure described or claimed with "a" or "an," it should be understood that these terms mean "one or more" unless context unambiguously requires a more restricted meaning. With respect to elements described as one or more within a set, it should be understood that all combinations within the set are contemplated. If aspects of the disclosure are described as "comprising" a feature, embodiments also are contemplated "consisting of or "consisting essentially of the feature. Additional features and variations of the disclosure will be apparent to those skilled in the art from the entirety of this application, and all such features are intended as aspects of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 depicts the mean absolute total serum iron concentration-time profile for subjects at Baseline (no exogenous iron) and treated with Treatment A (ferrous sulfate orally), Treatment B (Shohl' s solution orally, followed after 10 minutes by ferrous sulfate), Treatment C (SFP orally), Treatment D (Shohl' s solution orally, followed after 10 minutes by SFP orally), Treatment E (Shohl' s solution orally, followed immediately by SFP iron orally), and Treatment F (SFP intravenously (IV) over 4 hours).

[0015] Figure 2 depicts the mean baseline-corrected total serum iron concentration-time profile for subjects at Baseline and treated with Treatment A through F.

[0016] Figure 3A depicts a box plot of baseline-corrected total iron Cmax, and Figure 3B depicts a box plot of baseline-corrected AUCiast in subjects treated with Treatment A through F.

Figure imgf000007_0001
and 75% quartiles (interquartile range [IQR]); whiskers = lowest/highest values within 1.5*IQR of the lower/upper quartiles; dot symbols =

observations beyond whiskers; * = mean. [0017] Figure 4 depicts a box plot with 5 and 95 percentiles of bioavailability of iron in subjects treated with Treatment A through F. Solid line= median, dotted line = mean.

[0018] Figure 5 depicts mean values for serum hepcidin for subjects at baseline and treated with Treatment A through F.

DETAILED DESCRIPTION

[0019] The present disclosure relates to combination therapy comprising an iron compound such as SFP and a citrate compound. The combination therapy effectively treats iron deficiency (absolute and functional) and iron-sequestration syndromes, with and without anemia, including in subjects having iron deficiency with anemia and/or elevated hepcidin levels, such as those with IRIDA and/or chronic inflammatory disorders. Upon entry into the circulation, SFP can donate iron directly to transferrin without first requiring macrophage processing (Gupta et al. J Am Soc Nephrol 2010; 21: 429A; Pratt et al. / Clin Pharmacol 2016; DOI: 10.1002/jcph.819). Consequently, upon entry into the blood stream, SFP provides a means to bypass the hepcidin-induced obstruction of ferroportin iron export underlying IRIDA and other conditions having high hepcidin states (e.g., high plasma hepcidin concentrations). Citrate, a tricarboxylic anion, can complex with calcium in the gastrointestinal tract, opening intracellular tight junctions and permitting paracellular uptake of soluble complexes (Lemmer et al. Expert Opin Drug Deliv 2013; 10: 103-114; Nolan et al. Kidney Int 1990; 38: 937-941; Froment et al. Kidney Int 1989; 36: 978-984; Martinez-Palomo et al. J Cell Biol 1980; 87: 736-745; Coburn et al. Am J Kidney Dis 1991; 17: 708-711;

Drueke TB. Nephrol Dial Transplant 2002; 17 Suppl 2: 13-16). Ferric citrate, recently approved in Japan for control of hyperphosphatemia in patients with chronic kidney disease, increases transferrin saturation and serum ferritin over 12 weeks of administration (Gupta A. Pharmaceuticals 2014; 7: 990-998; Yokoyama et al. Clin J Am Soc Nephrol 2014; 9: 543- 552). Co-administering a citrate compound with an iron compound such as SFP provides in a synergistic increase in serum iron levels and whole blood (circulating) hemoglobin (Hgb) concentration that is greater than that with the iron compound administered alone. For example, one or more iron salts belonging to the SFP class co-administered with a citrate compound provides a synergistic increase in serum iron levels and whole blood Hgb that is greater than iron salts including SFP administered alone or iron compounds other than SFP co-administered with the citrate compound.

[0020] As used herein, the following definitions may be useful in aiding the skilled practitioner in understanding the disclosure. Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0021] The term "iron deficiency" refers to both absolute iron deficiency, wherein iron stores are absent, and total body iron is decreased, and functional iron deficiency, wherein iron stores are present, but the supply of iron from the stores is inadequate.

[0022] The term "soluble ferric pyrophosphate" or "SFP" refers to a soluble composition comprising a mixture of iron complexed to pyrophosphate and citrate with other excipients. For example, SFP can be a mixture of iron pyrophosphate citrate and sodium sulfate. In one aspect, SFP refers to FPC and comprises a mixed-ligand iron compound comprising iron chelated with citrate and pyrophosphate, optionally having the following formula:

Figure imgf000009_0001

Examples of SFP according to the present disclosure are described in U.S. Patent Nos.

7,816,404 and 8,178,709 and U.S. Provisional Patent No. 62/214,908, incorporated herein by reference in their entirety.

[0023] The term "chelate" refers to a metal cation and anions that surround the metal cation and are joined to it by electrostatic bonds, for example, a ferric iron cation surrounded by and joined by electrostatic bonds to both citrate and pyrophosphate anions.

[0024] The term "citrate compound" refers to a compound suitable for administering to a subject, e.g., a mammal such as a human, that yields a citrate anion (C6H5O7 ") at physiological pH. Examples of citrate compounds according to the disclosure include, but are not limited to, citric acid and salts of citrate such as sodium citrate, potassium citrate, calcium citrate, magnesium citrate, ammonium citrate, ferric citrate, and combinations of any of the foregoing. A citrate compound may solid, semi-solid, or a liquid (e.g., an aqueous solution such as Shohl's solution).

[0025] The terms "co-administering" and "combination therapy" mean that an iron compound and a citrate compound are administered in a manner that permits both to exert physiological effects during an overlapping period of time. In combination therapy comprising an iron compound and a citrate compound, the compounds may be administered in the same pharmaceutical composition (e.g., an admixture) or in separate compositions, via the same or different routes of administration. An iron compound and a citrate compound may be co-administered concurrently, i.e., simultaneously, or at different times, as long as both exert physiological effects during an overlapping period of time. For example, an iron compound and a citrate compound may both be administered to a subject within a time period of about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 4 hours, about 5 hours, or longer. If the iron compound and citrate compound are not co-administered concurrently, either the iron compound or citrate compound may be administered first. As long as the subsequent compound is administered while a physiological effect of the first administered compound is present, the iron compound and citrate compound are considered to be co-administered and used in combination therapy in accordance with the teachings of the disclosure.

[0026] The term "iron compound" refers to a compound containing iron (e.g., ferric or ferrous) that is suitable for administration to a subject, e.g., an orally active therapeutic compound. Examples of iron compounds include, but are not limited to, ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous succinate, ferric citrate, ferric pyrophosphate, soluble ferric pyrophosphate, ferric hydroxide, ferric pyrophosphate citrate, iron polymaltose, iron ascorbate, ferric (tri)maltol, heme iron polypeptide, iron EDTA, iron polysaccharide complex, and combinations thereof.

[0027] The terms "therapeutically effective amount" and "effective amount" refer to an amount of a single agent or combination therapy effective to achieve a desired biological, e.g., clinical, effect. A therapeutically effective amount varies with the nature of the disease being treated, the length of time that activity is desired, and the age and the condition of the subject. In one aspect, a therapeutically effective amount is an amount effective to increase serum iron levels and/or Hgb concentration compared to baseline. [0028] The term "synergistic increase" refers to an improvement in a therapeutic effect from administration of combination therapy comprising an iron compound and a citrate compound compared to the sum of the therapeutic effects of the iron compound and citrate compound alone or compared to the therapeutic effects of combination therapy comprising a non-SFP iron compound and the citrate compound.

[0029] The present disclosure provides pharmaceutical compositions, kits, methods of treatment, and medical uses comprising an iron compound and a citrate compound. In one aspect, the iron compound comprises a mixture of ferric pyrophosphate and sodium citrate. In another aspect, the iron compound comprises a mixture of ferric pyrophosphate, sodium pyrophosphate, ferric citrate, and sodium citrate. In various aspects, the iron compound comprises iron in an amount from 7% to 11% by weight, citrate in an amount of at least 14% by weight (e.g., 14% to 30% by weight), and pyrophosphate in an amount of at least 10% by weight (e.g., 10% to 20% by weight). Optionally, the iron compound comprises an iron composition described in any of U.S. Patent Nos. 7,816,404 and 8,178,709 or U.S.

Provisional Patent Application No. 62/214,908. For example, in one aspect, the iron compound is SFP that is a FPC composition comprising a mixed-ligand iron compound comprising iron chelated with citrate and pyrophosphate, optionally having the formula

and/or structure (I) described herein.

Figure imgf000011_0001

[0030] In one aspect, the citrate compound is selected from the group consisting of citric acid, sodium citrate, potassium citrate, calcium citrate, magnesium citrate, ammonium citrate, ferric citrate, combinations of any of the foregoing, and solutions thereof. In one aspect, the citrate compound is an aqueous solution comprising citric acid and sodium citrate.

Optionally, the citrate compound comprises citric acid or sodium citrate or both citric acid and sodium citrate, in a concentration of about 50 g/L to about 200 g/L, for example, about 50 g/L, about 60 g/L, about 70 g/L, about 80 g/L, about 90 g/L, about 100 g/L, about 110 g/L, about 120 g/L, about 130 g/L, about 140 g/L, about 150 g/L, about 160 g/L, about 170 g/L, about 180 g/L, about 190 g/L, or about 200 g/L. For example, in one aspect, the citrate compound comprises about 130 g/L to about 140 g/L citric acid and about 100 g/L hydrous sodium citrate. In one aspect, the citrate compound is Shohl's solution, a buffer of sodium citrate and citric acid commonly used for prolonged treatment of children with cystinuria and some forms of renal tubular acidosis.

[0031] The present disclosure provides a pharmaceutical composition comprising an iron compound and a citrate compound. In one aspect, the pharmaceutical composition comprises a dosage of an iron compound of about 0.2 mg iron to about 5 mg iron per kilogram body weight of the subject, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg, per kilogram body weight of the subject. Optionally, the pharmaceutical composition comprises an iron compound in an amount from about 5 mg iron to about 500 mg iron, for example, about 5 mg iron, about 10 mg iron, about 20 mg iron, about 30 mg iron, about 40 mg iron, about 50 mg iron, about 60 mg iron, about 70 mg iron, about 80 mg iron, about 90 mg iron, about 100 mg iron, about 150 mg iron, about 200 mg iron, about 250 mg iron, about 300 mg iron, about 350 mg iron, about 400 mg iron, about 450 mg iron, or about 500 mg iron. Optionally, the pharmaceutical composition comprises an iron concentration of about 110 μg/L or about 2 μΜ. In another aspect, the pharmaceutical composition comprises a dosage of a citrate compound of about 0.5 mmol to about 5 mmol per kilogram body weight of the subject, for example, about 0.5 mmol, about 0.6 mmol, about 0.7 mmol, about 0.8 mmol, about 0.9 mmol, about 1 mmol, about 1.5 mmol, about 2 mmol, about 2.5 mmol, about 3 mmol, about 3.5 mmol, about 4 mmol, about 4.5 mmol, or about 5 mmol, per kilogram body weight of the subject. Optionally, the pharmaceutical composition comprises a citrate compound in an amount from about 0.5 mmol to about 100 mmol, for example, about 0.5 mmol, about 1 mmol, about 2 mmol, about 3 mmol, about 4 mmol, 5 mmol, about 10 mmol, about 15 mmol, about 20 mmol, about 25 mmol, about 30 mmol, about 35 mmol, about 40 mmol, about 45 mmol, about 50 mmol, about 55 mmol, about 60 mmol, about 65 mmol, about 70 mmol, about 75 mmol, about 80 mmol, about 85 mmol, about 90 mmol, about 95 mmol, or about 100 mmol.

[0032] In one aspect, the pharmaceutical composition comprises an iron compound, a citrate compound, and a pharmaceutically acceptable carrier including, but not limited to, water, saline, phosphate buffered saline, dialysate, and combinations thereof. Other excipients, including buffering agents, dispersing agents, and preservatives, are known in the art and may be included in the pharmaceutical composition. Further examples of

components that may be employed in pharmaceutical compositions of the disclosure are presented in Remington's Pharmaceutical Sciences, 16th Ed. (1980) and 20th Ed. (2000), Mack Publishing Company, Easton, Pa. A pharmaceutical composition may be in any suitable dosage form including, but not limited to, tablets, capsules, liquids, lozenges, and gels. In one aspect, the pharmaceutical composition is for oral administration and is in the form of a tablet, capsule, gel, lozenge, or liquid. [0033] The present disclosure also provides a kit comprising an iron compound and a citrate compound in separate pharmaceutical compositions and instructions for coadministration of a therapeutically effective amount of the iron compound and citrate compound to a subject having iron deficiency, with or without anemia, e.g., IRIDA, using the methods described herein. In one aspect, a kit of the present disclosure comprises an iron compound and/or a citrate compound in a formulation to be administered orally. In one aspect, the kit comprises an iron compound in a solid form, for example, in a capsule or ampule that is broken, a blister pack that is pierced or peeled, or a sachet that is opened, to allow for the iron compound contained therein to be added to an aqueous solution for oral or parenteral administration. Optionally, an iron compound is formed into a mass, e.g., a tablet or wafer, that can be added directly to an aqueous solution, or stored within a dissolvable package that is soluble in an aqueous solution. In another aspect, the kit comprises an iron compound in a liquid form, for example, in an ampule, optionally an iron compound at a concentration of about 5 mg/mL iron to about 6 mg/mL iron (e.g., 5.44 mg/mL iron), in water, for example. In another aspect, a kit comprises a citrate compound which is an aqueous solution, e.g., Shohl's solution, optionally comprising about 640 mg/5mL citric acid and/or about 490 mg/5mL hydrous sodium citrate.

[0034] The present disclosure provides methods of treatment and medical uses to treat a subject in need thereof comprising co-administering a therapeutically effective amount of an iron compound and a citrate compound to the subject. In one aspect, a method of treating iron deficiency (e.g., anemia) comprises co-administering a therapeutically effective amount of an iron compound and a citrate compound to a subject in need thereof. In another aspect, the present disclosure provides an iron compound and a citrate compound for use in treating iron deficiency (e.g., anemia). In still another aspect, the present disclosure provides use of an iron compound and a citrate compound in the manufacture of a medicament for treating iron deficiency (e.g., anemia). In one aspect, the iron compound and citrate compound are administered concurrently, for example, admixed into a single composition prior to administration. In another aspect, the citrate compound is administered before the iron compound. In still another aspect, the iron compound is administered before the citrate compound. In combination therapy, the iron compound and citrate compound are administered in a manner that permits both to exert physiological effects during an overlapping period of time. In one aspect, the compounds are administered within 30 minutes of each other, for example, in a window of about 5 minutes to 15 minutes, e.g., 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, or 15 minutes, with either the iron compound or a citrate compound administered first. In various aspects, the iron compound and/or citrate compound is administered one, two, or three times per day. Optionally, the iron compound and/or citrate compound is administered at least one hour before or two hours after a meal. Optionally, the iron compound and/or citrate compound is administered orally, for example, both the iron compound and citrate compound are administered orally, or the citrate compound is administered orally and the iron compound is administered parenterally, e.g., by injection or infusion.

[0035] Purely by way of illustration, the methods of the present disclosure comprise administering (1) an iron compound in an amount from about 0.2 mg/kg/day iron to about 20 mg/kg/day iron or more, e.g., about 0.5 mg/kg/day, about 1 mg/kg/day, about 2 mg/kg/day, about 3 mg/kg/day, about 4 mg/kg/day, about 5 mg/kg/day, about 6 mg/kg/day, about 7 mg/kg/day, about 8 mg/kg/day, about 9 mg/kg/day, about 10 mg/kg/day, about 11 mg/kg/day, about 12 mg/kg/day, about 13 mg/kg/day, about 14 mg/kg/day, about 15 mg/kg/day, about 16 mg/kg/day, about 17 mg/kg/day, about 18 mg/kg/day, about 19 mg/kg/day, or about 20 mg/kg/day, of iron based on the body weight of the subject; and (2) a citrate compound in amount from about 0.5 mmol/kg/day to about 15 mmol/kg/day or more, based on the body weight of the subject. In some aspects, the daily dosage of an iron compound ranges from about 0.3 mg/kg to about 3 mg/kg iron, about 1 mg/kg to about 5 mg/kg iron, about 3 mg/kg to about 5 mg/kg iron, or about 5 mg/kg to about 10 mg/kg iron. In related aspects, the daily dosage of a citrate compound ranges from about 1 mmol/kg to about 5 mmol/kg, about 2 mmol/kg to about 10 mmol/kg, about 0.5 mmol/kg to about 3 mmol/kg, or about 1 mmol/kg to about 10 mmol/kg. The foregoing dosages for use in the methods, compositions, and kits of the present disclosure are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure.

[0036] In one aspect, the methods and medical uses of the disclosure comprise coadministering an iron compound and a citrate compound to a subject in need thereof in an amount effective to achieve and/or maintain a serum iron concentration of about 50 μg/dL to about 250 μg/dL, for example, about 50 μg/dL to about 150 μg/dL, about 50 μg/dL to about 120 μg/dL, about 60 μg/dL to about 175 μg/dL, about 100 μg/dL to about 250 μg/dL, or about 100 μg/dL to about 200 μg/dL. In some aspects, an iron compound and a citrate compound are co-administered in an amount effective to achieve or maintain a serum iron concentration at least above about 50 μg/dL, for example, above about 60 μg/dL, above about 70 μg/dL, above about 80 μg/dL, above about 90 μg/dL, above about 100 μg/dL, above about 110 μg/dL, or above about 120 μg/dL. In another aspect, the methods comprise coadministering an iron compound and a citrate compound in an amount effective to increase serum iron by at least about 25 μg/dL, for example, at least about 50 μg/dL at least about 75 μg/dL, or at least aboutlOO μg/dL, compared to before treatment with the combination therapy or to administering the iron compound without the citrate compound.

[0037] The present disclosure also provides methods of co-administering an iron compound and a citrate compound to a subject in need thereof in an amount effective to maintain or increase Hgb levels. For example, an iron compound and a citrate compound are co-administered in amount effective to increase Hgb levels high enough to adequately oxygenate the subject's tissues or provide improved oxygenation of the subject's tissues. Preferably, the dose of an iron compound and a citrate compound co-administered increases or maintains the Hgb level of the subject at a level of about 9 g/dL to 10 g/dL or greater, thereby reducing the need for blood transfusions, reducing fatigue, improving physical and cognitive functioning, improving cardiovascular function, improving exercise tolerance and enhancing quality of life. In various aspects, an iron compound and a citrate compound are co-administered in an amount effective to increase Hgb levels to or maintain Hgb levels at a target level ranging from 9 g/dL to 10 g/dL, at a target level ranging from 9 g/dL to 12 g/dL, at a target level ranging from 10 g/dL to 12 g/dL, at a target level ranging from 9 g/dL to 14 g/dL, at a target level ranging from 10 g/dL to 14 g/dL, or at a target level ranging from 12 g/dL to 14 g/dL. In addition, the disclosure provides for methods of co-administering a dose of an iron compound and a citrate compound effective to increase Hgb to or maintain Hgb at a target level of at least about 9 g/dL, of at least about 10 g/dL, of at least about 11 g/dL, of at least about 12 g/dL, of at least about 13 g/dL, or of at least about 14 g/dL. The disclosure also provides for methods of increasing Hgb concentration by at least about 0.1 g/dL, for example, at least about 0.1 g/dL, at least about 0.2 g/dL, at least about 0.3 g/dL, at least about 0.4 g/dL, at least about 0.5 g/dL, at least about 0.6 g/dL, at least about 0.7 g/dL, at least about 0.8 g/dL, at least about 0.9 g/dL, at least about 1.0, at least about 1.1 g/dL, at least about 1.2 g/dL, at least about 1.3 g/dL, at least about 1.4 g/dL, or at least about 1.5 g/dL, compared to before treatment. [0038] The disclosure also provides for any of the preceding methods or uses wherein an iron compound and a citrate compound are co-administered at a therapeutically effective dose that (i) increases at least one marker of iron status selected from the group consisting of serum iron, transferrin saturation, reticulocyte Hgb, serum ferritin, reticulocyte count, and whole blood Hgb; and (ii) decreases or eliminates the need for erythropoiesis stimulating agents (ESA) administration to achieve or maintain target hemoglobin levels, or the need for transfusion of whole blood, packed red blood cell or blood substitutes. In addition, any of the preceding methods or uses carried out in a subject can reduce fatigue, increase physical and cognitive ability, or improve exercise tolerance in the subject. The methods and uses of the disclosure can be used to increase serum iron, Hgb concentration, and/or another marker of iron status and maintain the increased level for a prolonged period of time, e.g., at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, or more.

[0039] In one aspect, the methods and medical uses of the disclosure comprise coadministering an iron compound and a citrate compound to a subject in need thereof in an amount effective to improve at least one serum iron pharmacokinetic parameter compared to an equivalent dosage of the iron compound administered without the citrate compound. In one aspect, co-administering an iron compound and a citrate compound to a subject increases the maximum serum iron concentration in a dose interval (Cmax) compared to the Cmax of an equivalent dosage of the iron compound administered without the citrate compound. In various aspects, an iron compound and a citrate compound are co-administered in an amount effective to increase the Cmax by at least 10 μg/dL, at least 20 μg/dL, at least 30 μg/dL, at least 40 μg/dL, at least 50 μg/dL, at least 60 μg/dL, at least 70 μg/dL, at least 80 μg/dL, at least 90 μg/dL, or at least 100 μg/dL, and/or by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, compared to the Cmax of an equivalent dosage of the iron compound administered without the citrate compound. In another aspect, co-administering an iron compound and a citrate compound to a subject increases the bioavailability of the iron compound compared to the bioavailability of an equivalent dosage of the iron compound administered without the citrate compound. In various aspects, an iron compound and a citrate compound are co-administered in an amount effective to increase the bioavailability by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, compared to the bioavailability of an equivalent dosage of the iron compound administered without the citrate compound. In still another aspect, co-administering an iron compound and a citrate compound to a subject increases the amount of iron absorbed from the iron compound compared to the amount of iron absorbed from an equivalent dosage of the iron compound administered without the citrate compound. In various aspects, an iron compound and a citrate compound are coadministered in an amount effective to increase the amount of iron absorbed by at least 0.5 mg, at least 1 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 3 mg, at least 3.5 mg, at least 4 mg, at least 4.5 mg, or at least 5 mg, and/or by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, compared to the amount of iron absorbed from an equivalent dosage of the iron compound administered without the citrate compound.

[0040] The methods, medical uses, pharmaceutical compositions, and kits of the present disclosure are used to treat a subject in need. Suitable subjects are those that would benefit from iron supplementation, including subjects suffering from iron deficiency or iron- sequestration syndrome(s), with or without anemia. Examples of anemia that may be treated using the pharmaceutical formulations, kits, and methods of the present disclosure include, but are not limited to, iron-deficiency anemia including IRIDA, anemia of chronic disease, anemia of chronic inflammation, renal anemia, cancer-related anemia, chemotherapy-related anemia, anemia caused by impaired production of ESA, anemia of inflammation, anemia in patients with inflammatory bowel disease, anemia in patients with congestive heart failure, anemia in chronic infections such as hepatitis B or hepatitis C, tuberculosis, HIV, anemia in patients with rheumatological diseases such as lupus and rheumatoid arthritis, microcytic anemia and/or hypochromic anemia. Suitable subjects include those exhibiting elevated serum and/or urinary hepcidin levels (e.g., serum/urinary hepcidin greater than 10 ng/mL or a hepcidin level that is inappropriately high given the patient's iron status) caused by conditions such as IRIDA, inflammatory conditions, chronic kidney disease, autoimmune diseases, chronic infections, rheumatologic diseases, inflammatory bowel disease, chronic disease, and cancer. [0041] The present disclosure will be more readily understood by reference to the following Examples, which are provided by way of illustration and are not intended to be limiting.

EXAMPLES

[0042] The following Examples describe clinical studies demonstrating that an iron compound co-administered with a citrate compound is safe and effective for the treatment of IRIDA.

Example 1

[0043] A Phase 1, open-label, randomized sequence, single-dose study was conducted to assess the safety, pharmacokinetics, and absolute bioavailability of iron from ferrous sulfate (FER-IN-SOL, Mead Johnson, Glenview, IL) or SFP (TRIFERIC, Rockwell Medical, Inc.) with and without a citrate compound (ORACIT Shohl's solution, CMC Pharma, Farmville, NC) in healthy male and female volunteers. A total of 14 healthy male and female subjects between the ages of 18 and 65 years, inclusive, who had a body mass index of <35 kg/m at screening were enrolled in the study. Subjects were required to have values within the reference ranges for each gender for hemoglobin (males, >13 g/dL; females, >12 g/dL), mean corpuscular volume, reticulocyte count, and serum ferritin (males, 23-336 ng/niL; females, 11-306 ng/niL); a TSAT >20%; and a serum TIBC concentration >250 g/dL at screening. Subjects agreed to discontinue use of all iron preparation for 14 days before baseline.

[0044] The study included a screening period (Days -28 to -1), a baseline period (Day 1), a treatment period (Days 2-12), and a follow-up period (Day 13 on), for a total duration of participation of up to 6 weeks for each subject. Eligible subjects were enrolled in the study on the next morning (Day 1) and underwent serial pharmacokinetic blood sampling over 24 hours (at 0, 1, 2, 4, 6, 8, 12, 16, and 24 hours) to determine diurnal variation of iron (baseline, no exogenous iron). An overview of the study design is provided in Table 1.

Figure imgf000019_0001

[0045] Subjects were confined to the clinical research unit (CRU) from the time of admission (Day -1) until the morning after administration of the last study treatment (Day 13). Subjects were given a low-iron diet while confined to the CRU. Subjects were required to fast overnight (nothing by mouth but water from midnight to 8 AM) on the evening before the baseline assessments (Day 1), on the evening before administration of the study treatments on Days 2, 4, 6, 8, 10, and 12, and on the evening before collection of the final blood samples on the morning of discharge from CRU (Day 13). Subjects were discharged from the CRU and from the study after all of the study assessments on the morning of Day 13 had been completed. Subjects received 5 oral iron treatments in randomized order on Days 2, 4, 6, 8, and 10: Treatment A: FER-IN-SOL, 3 mg iron/kg orally; Treatment B: Shohl' s solution, 0.7 mL/kg orally, followed after 10 minutes by FER- IN-SOL, 3 mg iron/kg orally; Treatment C: TRIFERIC, 3 mg iron/kg orally; Treatment D: Shohl' s solution, 0.7 mL/kg orally, followed after 10 minutes by TRIFERIC, 3 mg iron/kg orally; Treatment E: Shohl' s solution, 0.7 mL/kg orally, followed immediately by

TRIFERIC, 3 mg iron/kg orally; and Treatment F: TRIFERIC, 6.6 mg iron via continuous IV infusion over 4 hours. TRIFERIC was supplied in sterile 5-mL ampules containing

5.44 mg/mL of iron in water for injection (stock solution). Each ampule contained

27.2 mg/5 mL of TRIFERIC iron. ORACIT was supplied as 640 mg/5 mL citric acid and 490 mg/mL sodium citrate. FER-IN-SOL was supplied as a liquid preparation containing 15 mg iron/5 mL. Pharmacokinetic Analysis

[0046] Blood samples for pharmacokinetic determinations of iron parameters were obtained immediately before dosing (0 hour) and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after dosing on each dosing day. Each subject's iron stores were estimated using the serum soluble transferrin receptor (sTfR) and ferritin concentrations before administration (i.e., at 0 hour) of each of the study treatments. The primary pharmacokinetic endpoints were the mean absolute and baseline-corrected values for maximum drug concentration in serum (Cmax), time to reach maximum drug concentration (Tmax), time of last quantified concentration

area under the serum concentration-time curve from time zero to the time of the last

Figure imgf000020_0001

quantified concentration ,

Figure imgf000020_0002
area under the serum concentration-time curve from time zero to the end of the infusion of study drug (AUCo-end), area under the serum concentration- time curve from time zero extrapolated to infinity terminal phase rate constant (λζ),
Figure imgf000020_0003

terminal phase half-life (t½), systemic clearance (CL), and oral clearance (CL/F). The pharmacokinetic population for analysis included all enrolled subjects who received at least one dose of study drug and had sufficient pharmacokinetic samples to include in the pharmacokinetic assessments. The secondary pharmacokinetic endpoints were the absolute quantity of iron absorbed from each study treatment as assessed by comparison to the Cmax and of a single IV dose of TRIFERIC iron, the bioavailability of iron from each study

Figure imgf000020_0004

treatment as assessed by comparison of the amount of iron administered in each study treatment to the amount of TRIFERIC iron administered, the effect of study treatments on serum ferritin concentration and TSAT, and the effect of the study treatments on serum hepcidin concentration at 8 and 24 hours after dosing.

[0047] Serum concentrations and absolute and baseline-corrected pharmacokinetic parameters for sFe were derived for each study treatment from the serum concentration-time profiles, using noncompartmental methods in PHOENIX WINNONLIN version 6.3

(Pharsight Corporation, St. Louis, Missouri, USA). Summary statistics (arithmetic mean, coefficient of variation expressed as a percentage [CV%], SD of the arithmetic mean, minimum median, minimum, maximum, geometric mean, and CV% of the geometric mean) were presented for serum concentrations of sFe and for the pharmacokinetic parameters (except Tmax and Tiast) of sFe. Median, minimum, and maximum values were presented for Tmax and Tiast. An exploratory analysis, using clinical laboratory data, was also conducted because of the large number of pharmacokinetic samples that had sFe concentrations below the limit of quantitation (BLQ) of the bioanalytical assay. [0048] The baseline sFe profile (Day 1, no exogenous iron) demonstrated a clear cyclic pattern of endogenous iron concentration, with peak mean concentration observed

approximately 1 hour after the start of the study (8 AM), followed by a decrease to the lowest mean concentration at 12 hours (77.7 μg/dL), and then an increase in mean concentration at 24 hours (146 μg/dL) (Figure 1). Mean absolute sFe concentrations following a 4-hour infusion of 6.6 mg of TRIFERIC iron (Treatment F) peaked at the end of the infusion and remained higher than the baseline (Day 1) profile until the 16-hour sample. Mean absolute sFe concentrations peaked between 1 and 2 hours after administration of Fer-In-Sol iron oral solution alone (Treatment A) and FER-IN-SOL iron oral solution with Shohl' s solution (Treatment B). Oral TRIFERIC iron alone (Treatment C), showed serum iron concentrations similar to baseline. Oral TRIFERIC iron with Shohl' s solution (Treatments D and E) showed increases in serum iron greater than TRIFERIC alone (Treatment C).

[0049] Mean baseline-corrected sFe concentrations increased relative to the time-matched baseline (Day 1) values for all 6 of the study treatments (Figure 2). The predose and 24 hour samples from the baseline iron profile were generally higher than the predose and 24 hour values after exogenous administration of iron. This made it difficult to produce fully corrected time-matched serum iron values for all treatments. Thus, calculation of clearance parameters and -dependent parameters was possible for only a minority of subject iron

Figure imgf000021_0001

profiles. Mean baseline-corrected sFe concentration peaked at the end of the 4-hour IV infusion of TRIFERIC iron (Treatment F) and remained higher than the baseline profile until the 16-hour sample. Mean baseline-corrected sFe concentrations peaked at 4 hours after administration of the oral FER-IN-SOL iron treatments (Treatments A and B) and between 6 and 8 hours after administration of the oral TRIFERIC iron treatments (Treatments C-E). Concentrations returned to baseline at around 16 hours for each of the oral iron treatments.

[0050] The sFe concentration-time profiles that were obtained from an exploratory analysis using the sFe concentrations that were obtained from the clinical laboratory were similar to those obtained using the data from the bioanalytical assay. A high correlation (R >0.9) was observed between the concentrations determined by the clinical laboratory and the concentrations determined by the bioanalytical laboratory. No BLQ values were reported by the clinical laboratory. In contrast, 52 BLQ values were reported by the bioanalytical laboratory because the lower limit of quantitation (LLQ) was 50 μg/dL for the bioanalytical assay. In contrast, the LLQ for the clinical laboratory (autoanalyzer) was 5 μg/dL.

[0051] Absolute total serum iron pharmacokinetic parameters are summarized in Table 2.

Figure imgf000022_0001

[0052] Median absolute Tmax values for sFe were 2.0 hours (range, 1.0-4.0 hours) after administration of FER-IN-SOL iron oral solution alone (Treatment A), 1.0 hours (range, 1.0- 4.0 hours) after administration of FER-IN-SOL iron oral solution with Shohl's solution (Treatment B), 2.0 hours (range, 1.0-24.0 hours) after administration of oral TRIFERIC iron alone (Treatment C), 1.5 hours (range, 1.0-4.0 hours) after administration of oral TRIFERIC iron 10 minutes after Shohl's solution (Treatment D), and 1.0 hour (range, 1.0-6.0 hours) after administration of oral TRIFERIC iron immediately after Shohl's solution (Treatment E). The median absolute Tmax value for sFe was 4.05 hours (range, 4.05-4.08 hours) after IV administration of TRIFERIC iron.

[0053] Baseline-corrected total serum iron pharmacokinetic parameters are summarized in Table 3.

Figure imgf000023_0001

[0054] Baseline-corrected values for sFe Cmax and AUClast showed absorption and exposure relationships between iron treatments that were consistent with those based on absolute values, as did absolute and baseline-corrected values for sFe Cmax and AUCiast based on clinical laboratory data. Variability in serum iron parameters was observed across all subjects and within treatments, primarily due to the differences in baseline iron status. For the FER-IN-SOL treatments (Treatments A and B), the highest Cmax and AUCiast values were observed in those subjects with the lowest baseline hepcidin and ferritin concentrations.

[0055] Baseline-corrected sFe using the clinical laboratory assay gave more reliable estimates of Cmax and AUCiast because of the fewer BLQ values (Figure 3A and 3B).

Administration of TRIFERIC iron alone (Treatment C) showed minimal iron absorption. Coadministration of TRIFERIC iron with Shohl' s solution (Treatments D and E) showed a net increase in Cmax and AUClast values as compared with TRIFERIC iron alone (Treatment C). Intravenous TRIFERIC iron (Treatment F, reference treatment) also showed a range of Cmax and AUCiast values that were similar to those of FER-IN-SOL alone (Treatment A).

[0056] The baseline-corrected AUCiast value for the IV administration of 6.6 mg of TRIFERIC iron was used to estimate the absorption of iron from FER-IN-SOL and

TRIFERIC after oral administration with and without Shohl's solution. Because of the variability in baseline sFe, full correction of the basal iron led to many values BLQ. The best estimate of iron absorption was based on the clinical laboratory measurements of sFe, which resulted in the fewest values being BLQ. Iron absorption was variable across and within subjects. In general, absorption of ferrous iron (FER-IN-SOL) led to the highest quantity of iron absorption both without and with Shohl's solution (Figure 4). TRIFERIC iron administered orally demonstrated very little absorption as would be expected for a ferric iron product. However, co-administration of TRIFERIC iron with Shohl's solution led to an increase in iron absorption relative to oral TRIFERIC iron alone. Without intending to be bound by theory, the increase in absorption is likely mediated via paracellular pathways opened by the complexation of gastrointestinal (GI) calcium by citrate, increasing

permeability to molecules like TRIFERIC (SFP). Once in the blood, SFP can donate iron to transferrin for delivery to iron-requiring tissues.

[0057] The predose and 24-hour samples from the subjects' baseline profiles were generally higher than the predose and 24-hour samples from the profiles after subjects received exogenous iron administration. Despite attempts to collect fully time-matched baseline samples, the calculation of λζ and λζ-dependent parameters were possible for only a minority of profiles. Because both bioavailability and estimated amount of iron absorbed, as calculated from AUCo-t, depend on λζ, the results are absent or provided as "NC" (Not Calculated) in Tables 2 and 3. The bioavailability (F), assuming mean body weight of 70 kg to calculate the dose administered, and estimated amount of iron absorbed (Abs) from the treatments as calculated from baseline-corrected Cmax are summarized in Table 4.

Figure imgf000024_0001
Figure imgf000025_0001

[0058] Mean values for serum hepcidin at 8 hours were highest after administration of FER-IN-SOL iron oral solution alone (Treatment A) and lowest after administration of oral TRIFERIC iron alone (Treatment C) (Figure 5). Mean values for serum hepcidin at 8 hours were lower after administration of each of the oral TRIFERIC iron treatments (Treatments C, D, and E), as well as lower after IV administration of TRIFERIC iron (Treatment F), than at 8 hours in the baseline profile. In contrast, mean values for serum hepcidin at 8 hours were higher after administration of both FER-IN-SOL iron oral solution treatments (Treatments A and B) than at 8 hours in the baseline profile. Mean values for serum hepcidin had returned to baseline by 24 hours after administration of each of the 6 iron treatments. Mean and median values were within normal limits for serum hepcidin (<0.5-14.7 nm for males and <5 12.3 nm for premenopausal females) at 8 hours in the baseline profile and after

administration of each of the iron treatments. Values above the upper limit of normal for serum hepcidin were observed at 8 hours after administration of an iron treatment on 3 occasions in only 1 subject (after administration of FER-IN-SOL iron oral solution alone, after administration of Fer-In-Sol iron oral solution with Shohl's solution, and after administration of oral TRIFERIC iron 10 minutes after Shohl's solution). Values were well within normal limits for males at 24 hours after dosing.

Safety Study

[0059] Safety was evaluated through an assessment of the nature, frequency, and severity of adverse events and through assessments of vital signs and clinical laboratory tests

(hematology, serum chemistry, and urinalysis). The safety population for analysis included all subjects who signed the study- specific informed consent document and received at least one dose of study drug.

[0060] Blood samples for a safety serum iron profile (serum iron [sFe], ferritin, transferrin saturation [TSAT], and total iron-binding capacity [TIBC]) were obtained at 0 hour

(approximately 8 AM) and at 1, 2, 4, 6, 8, 12, 16, and 24 hours later on Day 1 (baseline, no exogenous iron) and immediately before dosing (0 hour) and at 1, 2, 4, 6, 8, 12, 16, and 24 hours after dosing on Days 2, 4, 6, 8, 10, and 12. Blood samples for determination of serum hepcidin concentrations were obtained at 0 hour and 8 and 24 hours on Days 1, 2, 4, 6, 8, 10, and 12.

[0061] Single doses of oral TRIFERIC iron (3 mg iron/kg) and FER-IN-SOL iron oral solution (3 mg iron/kg) were well tolerated when administered without and with Shohl' s solution. Gastrointestinal-related adverse events were the most commonly reported adverse events across all 5 of the oral study treatments. The incidence of Gl-related adverse events was greater after administration of FER-IN-SOL iron oral solution alone (50.0%, 7 of 14) than after administration of oral TRIFERIC iron alone (7.1%, 1 of 14). Co-administration of oral TRIFERIC iron with Shohl' s solution was associated with an increase in the incidence of Gl-related adverse events as compared with administration of oral TRIFERIC iron alone. At least one Gl-related adverse event was reported in 42.9% (6 of 14) of the subjects when oral TRIFERIC iron was administered 10 minutes after Shohl's solution and in 35.7% (5 of 14) of the subjects when oral TRIFERIC iron was administered immediately after Shohl's solution, whereas one Gl-related adverse event (nausea) was reported in 7.1% (1 of 14) of the subjects after administration of oral TRIFERIC iron alone.

[0062] The reported Gl-related events after co-administration of oral TRIFERIC iron with Shohl's solution were those that are commonly reported after administration of oral iron products (e.g., abdominal discomfort, abdominal distension, abdominal pain, defecation urgency, diarrhea, flatulence, nausea). No clinically meaningful difference in the incidence of any individual Gl-related event was observed based on the time of administration of oral TRIFERIC iron relative to Shohl's solution (i.e., 10 minutes after Shohl's solution or immediately after Shohl's solution). All of the Gl-related events were mild or moderate in severity. None of the Gl-related events were serious, and none led to premature

discontinuation of any subject from the study. Fewer subjects experienced Gl-related events when oral TRIFERIC iron was administered 10 minutes after (42.9%, 6 of 14) or

immediately after (35.7%, 5 of 14) Shohl's solution than when FER-IN-SOL iron oral solution was administered alone (50.0%, 7 of 14). Most notably, nausea was reported less frequently when oral TRIFERIC iron was administered 10 minutes after Shohl's solution (21.4%, 3 of 14) or immediately after Shohl's solution (14.3%, 2 of 14) than when

FER-IN-SOL iron oral solution was administered alone (42.9%, 6 of 14). The incidence of at least one Gl-related adverse event after co-administration of oral TRIFERIC iron with Shohl's solution, either 10 minutes after (42.9%, 6 of 14) or immediately after (35.7%, 5 of 14) administration of Shohl's solution, was comparable to that after co-administration of FER-IN-SOL iron oral solution with Shohl' s solution (35.7%, 5 of 14). Individual Gl-related events (e.g., diarrhea, flatulence, nausea) after co-administration of oral TRIFERIC iron with Shohl' s solution were reported at incidences comparable to those after co-administration of FER-IN-SOL iron solution with Shohl' s solution. No serious adverse events were reported, and there were no discontinuations due to adverse events after administration of any of the iron treatments.

[0063] The safety iron profile of oral TRIFERIC iron without and with Shohl' s solution was consistent with the administration of an iron-replacement product and with the safety iron profiles of FER-IN-SOL (with and without Shohl' s solution) and IV TRIFERIC iron. Increases from baseline in sFe and TSAT were observed after administration of oral

TRIFERIC iron without Shohl' s solution and after administration of oral TRIFERIC iron 10 minutes after or immediately after administration of Shohl' s solution, with concentrations of sFe higher after administration of oral TRIFERIC iron with Shohl' s solution than after administration of oral TRIFERIC iron without Shohl' s solution. Concentrations of sFe after administration of oral TRIFERIC iron, with or without Shohl' s solution, were lower than after administration of FER-IN-SOL iron oral solution without Shohl' s solution. Serum ferritin and TIBC concentrations remained relatively unchanged from baseline after administration of oral TRIFERIC iron without or with Shohl' s solution. None of the TSAT values exceeded 100% after administration of oral TRIFERIC iron without or with Shohl' s solution. No adverse effects of any study treatment were observed on systolic or diastolic blood pressure, pulse rate, or safety laboratory measurements.

Summary

[0064] The results of this study demonstrated that administration of TRIFERIC with Shohl' s solution increased iron absorption, potentially by the paracellular pathway. Shohl' s solution led to significant increases in iron absorption after administration of TRIFERIC iron (Treatment D) when administered 10 minutes before TRIFERIC iron or when administered sequentially (Treatment E). There was virtually no iron absorption when TRIFERIC 3 mg iron/kg was administered orally alone (Treatment C). The estimated quantities of iron from Shohl' s plus TRIFERIC iron ranged from 0.8 mg iron to 11.1 mg iron, with a mean of 4.6 mg iron for Treatment D and 5.5 mg iron for Treatment E. Baseline (Day 1) serum iron concentrations were variable across subjects and may have reflected differences in body iron status prior to admission to the CRU as evidenced by the range of baseline hepcidin concentrations. Total serum iron after IV infusion of TRIFERIC 6.6 mg (Treatment F) showed an increase, with peak concentration at approximately 4 hours and a return to baseline concentrations by 16 hours after the start of infusion. Administration of 3 mg iron/kg FER-IN-SOL led to higher iron exposure (Treatment A) than 3 mg iron /kg FER-IN- SOL with Shohl's solution (Treatment B). Serum iron parameters were similar between the bioanalytical laboratory and the clinical laboratory determinations, with fewer BLQ values obtained by the clinical laboratory measurement of sFe. TRIFERIC iron without and with co-administered Shohl's solution was generally well tolerated. Adverse events were generally mild to moderate, occurred primarily in the GI system, abated rapidly after dosing, and were similar in frequency to FER-IN-SOL administered with Shohl's solution.

[0065] The clinical study provided evidence that co-administration of SFP with a citrate compound results in paracellular absorption of SFP and subsequent donation of iron to transferrin for utilization by the erythroid marrow and other tissues. The pharmacokinetic and safety results from this study supported that SFP co-administered with a citrate compound can provide sufficient iron to improve the anemia in patients with constitutive elevations of hepcidin, such as patients with IRIDA and anemia of chronic inflammation. Without co-administration of a citrate compound, minimal amounts of SFP were absorbed, but with the citrate compound, mean SFP iron absorption was about 4 mg, or approximately four times the daily iron requirement of an adult male ( about 1 mg/day). For patients with IRIDA or anemia of chronic inflammation, this magnitude of paracellular iron absorption should be sufficient to correct the anemia, raising the hemoglobin concentration to normal or near- normal levels.

Example 2

[0066] A Phase 2, open-label, 3-period study assessing the safety, efficacy, and

pharmacokinetics of SFP (TRIFERIC, Rockwell Medical, Inc.) and a citrate compound (ORACIT Shohl's solution, CMC Pharma, Farmville, NC) administered orally to patients with IRIDA is conducted. A total of 28 patients stratified by 4 age groups (age 0 to <6 years, age 6 to <12 years, age 12 to <18 years, and age >18 years) is studied. The study design schematic is shown in Table 5.

Figure imgf000029_0001

[0067] Patients are enrolled only if a patient has: (1) history of congenital hypochromic microcytic anemia; (2) mean corpuscular volume (MCV) <75 fL at screening; (3) serum transferrin saturation <15% at screening; (4) history of no or incomplete response to oral iron therapy and intravenous iron administration; (5) history of an elevated hepcidin concentration with respect to the range found in iron-deficiency anemia; (6) documentation of homozygous or compound heterozygous pathogenic mutations in TMPRSS6 from a CLIA-certified laboratory; (7) appropriate laboratory values for their disease state at screening (per investigator judgment); and (8) no significant abnormal findings on physical examination at screening that would preclude participation in the study (per investigator judgment). Oral and IV iron products, including oral multivitamins containing iron, are prohibited from 2 weeks prior to Visit 2 until all blood samples have been collected after the Follow-up/Early Termination Visit. Blood transfusions are prohibited from 3 months prior to Visit 2.

Aluminum-containing compounds (e.g., MAALOX, ALTERNAGEL, ALU-CAP,

DIALUME, AMPHOJEL, ALU-TAB, ALOH-GEL, etc.) are prohibited from Day 1 of the study through the date of the patient's last dose of the citrate compound.

[0068] Ferrous sulfate (FER-IN-SOL, Mead Johnson, Glenview, IL) is supplied as 50-mL bottles containing 15 mg Fe/mL and administered at a dose of 3 mg Fe/kg at Visits 2 and 3. At Visit 3, the dose is given 5 minutes to 15 minutes after the dose of the citrate compound. The citrate compound is supplied as 500-mL bottles containing citric acid USP 640 mg/5 mL and hydrous sodium citrate USP 490 mg/5 mL. Other commercially-available preparations of Shohi's solution or other citrate compounds may also be used. The Shohi's solution is administered at 0.67 mmol/kg at Visits 3-4. The SFP is supplied as sterile 5-mL ampules containing 5.44 mg/mL of iron in water. Each 5-mL ampule contains 27.2 mg of SFP iron. The SFP is administered at a dose of 3 mg Fe/kg at Visit 4, 5 minutes to 15 minutes after the dose of the citrate compound. At each of Visits 5, 7, 9, 10, and 11, sufficient amounts of the SFP and citrate compound to provide at least 60 days of dosing are dispensed to the patient. On study visit days, patients do not take their SFP and citrate compound doses until after the study visit. Patients stop taking SFP and the citrate compound after Visit 12.

[0069] Blood samples are obtained at various times to analyze for changes in CBC, reticulocyte count, the reticulocyte Hgb concentration (CHr), the serum iron profile (serum iron, ferritin, transferrin TSAT, TIBC, and UIBC), other serum iron parameters (TBI, NTBI, and LPI), and soluble transferrin receptor (sTfR) and hepcidin concentrations. Patients are also monitored for safety parameters, including adverse events, clinical laboratory parameters, and vital signs, during the study.

[0070] In Period 1 (Visits 2-4, Weeks 1-3), patients undergo oral iron absorption testing during 3 visits to confirm that they adequately absorb iron from the SFP when it is administered with the citrate compound. Patients are dosed during Period 1 as follows: oral FeS04, 3 mg Fe/kg body weight at Visit 2; oral citrate compound, 0.67 mmol/kg body weight, followed after 5 minutes to 15 minutes by oral FeS04, 3 mg Fe/kg body weight at Visit 3; and oral citrate compound, 0.67 mmol/kg body weight, followed after 5 minutes to 15 minutes by oral SFP, 3 mg Fe/kg body weight at Visit 4. At each of Visits 2-4, blood samples for serum iron parameters (serum iron, TSAT, TBI, NTBI, and LPI) are collected within 30 minutes prior to the oral iron dose and at 1 hr, 2 hr, and 4 hr following the oral iron dose. Following Visit 4, the patient's Visit 4, serum iron Cmax is compared to the Visit 4, Hr 0 serum iron concentration. If the Visit 4, serum iron Cmax is >100 g/dL higher than the Visit 4, Hr 0 serum iron concentration, the patient is designated a "SFP responder" and proceeds to Period 2. If not, the patient proceeds to the early termination visit to occur approximately 1 week after Visit 4.

[0071] In Period 2 (dose titration; Visits 5-9, Weeks 4-20), Period 1 "SFP responders" receive SFP and the citrate compound orally up to 3 times per day for 4 months, titrated as needed based on laboratory results and patient tolerance, to determine whether their hemoglobin levels respond to this treatment. Venous blood is collected and analyzed for hematology, reticulocyte count, CHr, chemistry, the serum iron profile, and sTfR and hepcidin concentrations. Following Visit 9, the patient's Visit 9 hemoglobin level is compared to the Visit 5 hemoglobin level. If the Visit 9 hemoglobin level is >1 g/dL higher than the Visit 5 level, the patient is designated a "hemoglobin responder" and proceeds to Period 3. If not, the patient proceeds to the early termination visit to occur within approximately 1 week after Visit 9.

[0072] In Period 3 (hemoglobin maintenance, Visits 10-12, Weeks 21-44), Period 2 "hemoglobin responders" receive SFP and the citrate compound orally up to 3 times per day for an additional 6 months to confirm that the hemoglobin response observed in Period 2 is sustainable. During Period 3, the dose and frequency of the SFP and the citrate compound continue to be titrated as needed based on laboratory results and patient tolerance. Venous blood is collected and analyzed for hematology, reticulocyte count, CHr, chemistry, the serum iron profile, and sTfR and hepcidin concentrations. During Periods 2 and 3, it is recommended that the patients take the SFP and citrate compound orally at least one hour before or two hours after meals.

[0073] A follow-up visit occurs approximately 1 week after Visit 12. Blood is collected and analyzed for hematology, chemistry, and the serum iron profile. The reticulocyte count, CHr, and sTfR and hepcidin concentrations are collected if not collected within the previous 30 days. The duration from screening to the last study visit is approximately 12 months.

[0074] The primary efficacy endpoint is the change from baseline in hemoglobin concentration, e.g., at 4 months. Key secondary efficacy endpoints include: (1) change from baseline in serum iron and TSAT, e.g., at 4 months; (2) change from baseline in Hgb, RBC, MCV, reticulocyte count, CHr, serum iron, TIBC, ferritin, UIBC, TSAT, and sTfR and hepcidin concentrations, e.g., every 4 weeks and at end-of-treatment (EoT); (3) incidence of hemoglobin responders (patients with an increase from baseline in Hgb concentration >1.0 g/dL), e.g., every 4 weeks and at EoT; (4) serum iron Cmax, e.g., at Visit 4; and (5) incidence of SFP responders (patients with a maximal increase from baseline in serum iron

concentration >100 μg/dL), e.g., at Visit 4. Safety endpoints include incidence of treatment- emergent adverse events and serious adverse events and changes in clinical laboratory tests, vital signs, and weight.

[0075] Combination therapy comprising SFP and a citrate compound produces a sustained increase in serum iron of >100 μg/dL and in hemoglobin concentration of ≥1 g/dL in a majority of the treated patients. Co-administering SFP and a citrate compound is more effective at increasing serum iron and hemoglobin concentrations than combination therapy comprising conventional ferrous sulfate and the citrate compound. Without being bound to theory, in patients with IRIDA, oral co-administration of SFP with the citrate compound bypasses the hepcidin-mediated block of enterocyte iron uptake by permitting paracellular absorption (i) of intact SFP that reaches the proximal duodenum and jejunum, with subsequent direct donation of iron to transferrin, and (ii) of iron derived from SFP. The therapeutic efficacy of combination therapy comprising SFP and a citrate compound in IRIDA patients previously unresponsive to iron therapy demonstrates the ability of such combination therapy to treat a wide variety of patients suffering from iron deficiency, anemia, and/or high hepcidin levels.

[0076] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this disclosure that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WHAT IS CLAIMED:
1. A pharmaceutical composition comprising an iron compound and a citrate compound.
2. The pharmaceutical composition of claim 1, wherein the iron compound is selected from ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous succinate, ferric hydroxide, ferric citrate, ferric pyrophosphate, soluble ferric pyrophosphate, ferric pyrophosphate citrate, iron polymaltose, iron ascorbate, ferric (tri)maltol, heme iron polypeptide, iron EDTA, iron polysaccharide, and combinations thereof.
3. The pharmaceutical composition of claim 1 or 2, wherein the iron compound comprises soluble ferric pyrophosphate (SFP).
4. The pharmaceutical composition of claim 3, wherein the SFP donates iron rapidly to transferrin after absorption via the paracellular pathway.
5. The pharmaceutical composition of claim 3 or 4, wherein the SFP is a ferric pyrophosphate citrate that comprises iron in an amount from 7% to 11% by weight, citrate in an amount from 14% to 30% by weight, and pyrophosphate in an amount from 10% to 20% by weight.
6. The pharmaceutical composition of any of claims 1-5, wherein the citrate compound is selected from the group consisting of citric acid, sodium citrate, potassium citrate, calcium citrate, magnesium citrate, ammonium citrate, combinations of any of the foregoing, and solutions thereof.
7. The pharmaceutical composition of any of claims 1-6, wherein the citrate compound comprises citric acid and sodium citrate.
8. The pharmaceutical composition of claim 7, wherein the citrate compound comprises about 128 mg/mL citric acid and about 98 mg/mL sodium citrate.
9. The pharmaceutical composition of any of claims 1-8, wherein the citrate compound is an aqueous solution.
10. The pharmaceutical composition of claim 9, wherein the citrate compound is Shohl's solution.
11. The pharmaceutical composition of any of claims 1-10, wherein the composition is for oral administration.
12. The pharmaceutical composition of any of claims 1-11, comprising a dosage of the iron compound of about 5 mg iron to about 500 mg iron.
13. The pharmaceutical composition of any of claims 1-12, comprising a dosage of the citrate compound of about 0.5 mmol to about 100 mmol.
14. A kit comprising an iron compound and a citrate compound and instructions for coadministration of a therapeutically effective amount of the iron compound and the citrate compound to a subject having iron deficiency.
15. The kit of claim 14, wherein the iron compound is selected from ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous succinate, ferric hydroxide, ferric citrate, ferric pyrophosphate, soluble ferric pyrophosphate, ferric pyrophosphate citrate, iron polymaltose, iron ascorbate, ferric (tri)maltol, heme iron polypeptide, iron EDTA, iron polysaccharide, and combinations thereof.
16. The kit of claim 14 or 15, wherein the iron compound comprises soluble ferric pyrophosphate (SFP).
17. The kit of claim 16, wherein the SFP donates iron rapidly to transferrin after absorption via the paracellular pathway.
18. The kit of claim 16 or 17, wherein the SFP is a ferric pyrophosphate citrate that comprises iron in an amount from 7% to 11% by weight, citrate in an amount from 14% to 30% by weight, and pyrophosphate in an amount from 10% to 20% by weight.
19. The kit of any of claims 16-18, comprising SFP in an ampule comprising about 5.44 mg/mL of iron in water.
20. The kit of any of claims 14-19, wherein the citrate compound is selected from the group consisting of citric acid, sodium citrate, potassium citrate, calcium citrate, magnesium citrate, ammonium citrate, combinations of any of the foregoing, and solutions thereof.
21. The kit of any of claims 14-20, wherein the citrate compound comprises citric acid and sodium citrate.
22. The kit of claim 21, wherein the citrate compound comprises about 128 mg/mL citric acid and about 98 mg/mL sodium citrate.
23. The kit of any of claims 14-22, wherein the citrate compound is an aqueous solution.
24. The kit of claim 23, wherein the citrate compound is Shohl's solution.
25. The kit of any of claims 14-24, wherein the citrate compound comprises about 640 mg/5 mL citric acid and about 490 mg/5 mL hydrous sodium citrate in water.
26. The kit of any of claims 14-25, wherein the iron compound and/or citrate compound is in pharmaceutical formulation for oral administration.
27. A method of treating iron deficiency or iron sequestration syndrome in a subject in need thereof comprising administering the pharmaceutical composition of any of claims 1-13 to the subject.
28. A method of treating iron deficiency or iron sequestration syndrome in a subject in need thereof comprising co-administering a therapeutically effective amount of an iron compound and a citrate compound to the subject.
29. An iron compound and a citrate compound for use in treatment of anemia in a patient.
30. Use of an iron compound and a citrate compound in the manufacture of a medicament for treating iron deficiency in a patient.
31. A method of increasing serum iron in a subject in need thereof, comprising coadministering a therapeutically effective amount of an iron compound and a citrate compound to the subject.
32. A method of increasing hemoglobin levels in a subject in need thereof, comprising coadministering a therapeutically effective amount of an iron compound and a citrate compound to the subject.
33. The method or use of any of claims 27-32, comprising co-administering the iron compound and citrate compound in an amount effective to increase serum iron in the subject by at least 100 μg/dL compared to baseline.
34. The method or use of any of claims 27-33, comprising co-administering the iron compound and citrate compound in an amount effective to increase transferrin saturation compared to baseline.
35. The method or use of any of claims 27-34, comprising co-administering the iron compound and citrate compound in an amount effective to increase hemoglobin
concentration by at least 1 g/dL compared to baseline.
36. The method or use of any of claims 27-35, comprising administering the iron compound and citrate compound concurrently, optionally in an admixture.
37. The method or use of any of claims 27-36, comprising administering the iron compound after the citrate compound.
38. The method or use of any of claims 27-37, comprising administering the iron compound less than 15 minutes after the citrate compound is administered.
39. The method or use of any of claims 27-38, comprising co-administering the iron compound and citrate compound at least one hour before or two hours after a meal.
40. The method or use of any of claims 27-39, comprising administering the iron compound at a dosage of about 0.2 mg Fe to about 5 mg Fe per kg bodyweight per day in single or divided doses.
41. The method or use of claim 40, comprising administering the iron compound at a dosage of about 3 mg Fe/kg body weight.
42. The method or use of any of claims 27-41, comprising administering the citrate compound at a dosage of about 0.5 mmol to about 2 mmol per kg bodyweight.
43. The method or use of any of claims 27-42, comprising co-administering the iron compound and citrate compound up to three times per day.
44. The method or use of any of claims 27-43, wherein the subject has iron-refractory iron deficient anemia.
45. The method or use of any of claims 27-44, wherein the subject has an elevated serum or urinary hepcidin level, optionally a hepcidin level of at least 10 ng/mL.
46. The method or use of any of claims 27-45, wherein the iron compound is selected from ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous succinate, ferric hydroxide, ferric citrate, ferric pyrophosphate, soluble ferric pyrophosphate, ferric pyrophosphate citrate, iron polymaltose, iron ascorbate, ferric (tri)maltol, heme iron polypeptide, iron EDTA, iron polysaccharide, and combinations thereof.
47. The method or use of any of claims 27-46, wherein the iron compound comprises soluble ferric pyrophosphate (SFP).
48. The method or use of claim 47, wherein the SFP donates iron rapidly to transferrin after absorption via the paracellular pathway.
49. The method or use of claim 47 or 48, wherein the SFP is a ferric pyrophosphate citrate that comprises iron in an amount from 7% to 11% by weight, citrate in an amount from 14% to 30% by weight, and pyrophosphate in an amount from 10% to 20% by weight.
50. The method or use of any of claims 27-49, wherein the citrate compound is selected from the group consisting of citric acid, sodium citrate, potassium citrate, calcium citrate, magnesium citrate, ammonium citrate, combinations of any of the foregoing, and solutions thereof.
51. The method or use of any of claims 27-50, wherein the citrate compound comprises citric acid and sodium citrate.
52. The method or use of claim 51, wherein the citrate compound comprises about 128 mg/mL citric acid and about 98 mg/mL sodium citrate.
53. The method or use of any of claims 27-52, wherein the citrate compound is an aqueous solution.
54. The method or use of any of claims 27-53, wherein the citrate compound is Shohl's solution.
55. The method or use of any of claims 27-54, wherein the iron compound and/or citrate compound is administered orally.
56. The method or use of any of claims 27-55, wherein the iron compound and citrate compound are co-administered in an amount effective to increase the maximum serum iron concentration in a dose interval (Cmax), compared to the Cmax of an equivalent dosage of the iron compound administered without the citrate compound.
57. The method or use of any of claims 27-56, wherein the iron compound and citrate compound are co-administered in an amount effective to increase the bioavailability of the iron compound, compared to the bioavailability of an equivalent dosage of the iron compound administered without the citrate compound.
58. The method or use of any of claims 27-57, wherein the iron compound and citrate compound are co-administered in an amount effective to increase the amount of iron absorbed from the iron compound, compared to the amount of iron absorbed from an equivalent dosage of the iron compound administered without the citrate compound.
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