EP3399970A1 - Polythérapie comprenant composé de fer et composé de citrate - Google Patents

Polythérapie comprenant composé de fer et composé de citrate

Info

Publication number
EP3399970A1
EP3399970A1 EP17703245.5A EP17703245A EP3399970A1 EP 3399970 A1 EP3399970 A1 EP 3399970A1 EP 17703245 A EP17703245 A EP 17703245A EP 3399970 A1 EP3399970 A1 EP 3399970A1
Authority
EP
European Patent Office
Prior art keywords
iron
compound
citrate
sfp
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17703245.5A
Other languages
German (de)
English (en)
Inventor
Ajay Gupta
Gary BRITTENHAM
Raymond Pratt
Vivian H. LIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rockwell Medical Inc
Original Assignee
Rockwell Medical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rockwell Medical Inc filed Critical Rockwell Medical Inc
Publication of EP3399970A1 publication Critical patent/EP3399970A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present disclosure relates to combination therapy comprising an iron compound and a citrate compound for use in treating iron deficiency.
  • 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
  • iron deficiency anemia is therefore particularly debilitating.
  • 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.
  • iron-refractory iron deficiency anemia 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
  • TMPRSS6 matriptase-2
  • MT-2 matriptase-2
  • 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.
  • 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).
  • 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).
  • 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.
  • Soluble ferric pyrophosphate 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.
  • 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.
  • the present disclosure is directed to combination therapy comprising an iron compound and a citrate compound.
  • the disclosure provides pharmaceutical compositions comprising an iron compound and a citrate compound, optionally compositions for oral administration.
  • 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.
  • 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.
  • 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.
  • the kit comprises an iron compound in an ampule containing about 5.44 mg/niL Fe in water.
  • 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.
  • 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.
  • the iron compound and/or citrate compound is in a pharmaceutical composition for oral administration.
  • 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.
  • the present disclosure provides an iron compound and a citrate compound for use in treating iron deficiency.
  • the present disclosure provides use of an iron compound and a citrate compound in the manufacture of a medicament for treating iron deficiency.
  • a method of increasing serum iron comprises co-administering a
  • 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.
  • 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.
  • the iron compound is administered first.
  • the citrate compound is administered first.
  • the iron compound and/or citrate compound is administered orally, for example, both the iron compound and citrate compound are administered orally.
  • the iron compound and/or citrate compound is administered one, two, or three times per day.
  • the iron compound and/or citrate compound is administered at least one hour before or two hours after a meal.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • iron deficiency absolute and functional
  • iron-sequestration syndrome(s) with or without anemia
  • 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
  • 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).
  • 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).
  • 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).
  • Treatment A ferrrous sulfate orally
  • Treatment B Treatment B
  • 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
  • Treatment F SFP intravenously (IV) over 4 hours).
  • Figure 2 depicts the mean baseline-corrected total serum iron concentration-time profile for subjects at Baseline and treated with Treatment A through F.
  • Figure 3A depicts a box plot of baseline-corrected total iron Cmax
  • Figure 5 depicts mean values for serum hepcidin for subjects at baseline and treated with Treatment A through F.
  • 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.
  • 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).
  • 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;
  • 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.
  • 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.
  • soluble ferric pyrophosphate refers to a soluble composition comprising a mixture of iron complexed to pyrophosphate and citrate with other excipients.
  • SFP can be a mixture of iron pyrophosphate citrate and sodium sulfate.
  • SFP refers to FPC and comprises a mixed-ligand iron compound comprising iron chelated with citrate and pyrophosphate, optionally having the following formula:
  • 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.
  • 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 (C 6 H 5 O 7 " ) at physiological pH.
  • a subject e.g., a mammal such as a human
  • citrate anion C 6 H 5 O 7 "
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a therapeutically effective amount refers 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.
  • a therapeutically effective amount is an amount effective to increase serum iron levels and/or Hgb concentration compared to baseline.
  • 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.
  • the present disclosure provides pharmaceutical compositions, kits, methods of treatment, and medical uses comprising an iron compound and a citrate compound.
  • the iron compound comprises a mixture of ferric pyrophosphate and sodium citrate.
  • the iron compound comprises a mixture of ferric pyrophosphate, sodium pyrophosphate, ferric citrate, and sodium citrate.
  • 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).
  • 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.
  • 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
  • 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.
  • the citrate compound is an aqueous solution comprising citric acid and sodium citrate.
  • 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.
  • the citrate compound comprises about 130 g/L to about 140 g/L citric acid and about 100 g/L hydrous sodium citrate.
  • 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.
  • the present disclosure provides a pharmaceutical composition comprising an iron compound and a citrate compound.
  • 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.
  • 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.
  • the pharmaceutical composition comprises an iron concentration of about 110 ⁇ g/L or about 2 ⁇ .
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • a pharmaceutical composition may be in any suitable dosage form including, but not limited to, tablets, capsules, liquids, lozenges, and gels.
  • the pharmaceutical composition is for oral administration and is in the form of a tablet, capsule, gel, lozenge, or liquid.
  • kits 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.
  • a kit of the present disclosure comprises an iron compound and/or a citrate compound in a formulation to be administered orally.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure provides an iron compound and a citrate compound for use in treating iron deficiency (e.g., anemia).
  • 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).
  • the iron compound and citrate compound are administered concurrently, for example, admixed into a single composition prior to administration.
  • the citrate compound is administered before the iron compound.
  • the iron compound is administered before the citrate compound.
  • the iron compound and citrate compound are administered in a manner that permits both to exert physiological effects during an overlapping period of time.
  • 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.
  • the iron compound and/or citrate compound is administered one, two, or three times per day.
  • the iron compound and/or citrate compound is administered at least one hour before or two hours after a meal.
  • 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.
  • 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
  • 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.
  • 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 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 ⁇ g/dL to about 250 ⁇ g/dL, for example, about 50 ⁇ g/dL to about 150 ⁇ g/dL, about 50 ⁇ g/dL to about 120 ⁇ g/dL, about 60 ⁇ g/dL to about 175 ⁇ g/dL, about 100 ⁇ g/dL to about 250 ⁇ g/dL, or about 100 ⁇ g/dL to about 200 ⁇ g/dL.
  • 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 ⁇ g/dL, for example, above about 60 ⁇ g/dL, above about 70 ⁇ g/dL, above about 80 ⁇ g/dL, above about 90 ⁇ g/dL, above about 100 ⁇ g/dL, above about 110 ⁇ g/dL, or above about 120 ⁇ g/dL.
  • the methods comprise coadministering an iron compound and a citrate compound in an amount effective to increase serum iron by at least about 25 ⁇ g/dL, for example, at least about 50 ⁇ g/dL at least about 75 ⁇ g/dL, or at least aboutlOO ⁇ g/dL, compared to before treatment with the combination therapy or to administering the iron compound without the citrate compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ESA erythropoiesis stimulating agents
  • 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.
  • 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.
  • 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.
  • an iron compound and a citrate compound are co-administered in an amount effective to increase the Cmax by at least 10 ⁇ g/dL, at least 20 ⁇ g/dL, at least 30 ⁇ g/dL, at least 40 ⁇ g/dL, at least 50 ⁇ g/dL, at least 60 ⁇ g/dL, at least 70 ⁇ g/dL, at least 80 ⁇ g/dL, at least 90 ⁇ g/dL, or at least 100 ⁇ g/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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • IRIDA e.g., serum/urinary hepcidin greater than 10 ng/mL or a hepcidin level that is inappropriately high given the patient's iron status
  • conditions such as IRIDA, inflammatory conditions, chronic kidney disease, autoimmune diseases, chronic infections, rheumatologic diseases, inflammatory bowel disease, chronic disease, and cancer.
  • 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.
  • 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).
  • Table 1 An overview of the study design is provided in Table 1.
  • 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.
  • CRU clinical research unit
  • 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
  • TRIFERIC iron 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.
  • 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 C max and of a single IV dose of TRIFERIC iron, the bioavailability of iron from each study
  • 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).
  • 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.
  • 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.
  • TRIFERIC iron alone showed minimal iron absorption.
  • Coadministration of TRIFERIC iron with Shohl' s solution showed a net increase in C max and AUC last values as compared with TRIFERIC iron alone (Treatment C).
  • Intravenous TRIFERIC iron (Treatment F, reference treatment) also showed a range of C max and AUCiast values that were similar to those of FER-IN-SOL alone (Treatment A).
  • 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
  • SFP TRIFERIC
  • 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
  • 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.
  • 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.
  • FER-IN-SOL iron oral solution was administered alone (42.9%, 6 of 14).
  • 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.
  • 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.
  • 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.
  • 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.
  • sufficient amounts of the SFP and citrate compound to provide at least 60 days of dosing are dispensed to the patient.
  • 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.
  • 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.
  • 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 FeS0 4 , 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 FeS0 4 , 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.
  • serum iron parameters serum iron, TSAT, TBI, NTBI, and LPI
  • serum iron C max is compared to the Visit 4, Hr 0 serum iron concentration. If the Visit 4, serum iron C max 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 C max , e.g., at Visit 4; and (5) incidence of SFP responders (patients with a maximal increase from baseline in serum iron
  • Safety endpoints include incidence of treatment- emergent adverse events and serious adverse events and changes in clinical laboratory tests, vital signs, and weight.
  • Combination therapy comprising SFP and a citrate compound produces a sustained increase in serum iron of >100 ⁇ g/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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une polythérapie comprenant un composé de fer, de préférence le pyrophosphate ferrique soluble (SFP), en combinaison avec un composé de citrate. L'invention concerne également des procédés d'utilisation de la polythérapie dans le traitement de carence en fer, avec ou sans anémie, y compris l'anémie ferriprive réfractaire au traitement par le fer et d'autres syndromes de séquestration de fer, et des compositions pharmaceutiques et des kits comprenant SFP ou un autre composé de fer et un composé de citrate.
EP17703245.5A 2016-01-06 2017-01-05 Polythérapie comprenant composé de fer et composé de citrate Withdrawn EP3399970A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201662275487P 2016-01-06 2016-01-06
US201662432564P 2016-12-09 2016-12-09
PCT/US2017/012300 WO2017120311A1 (fr) 2016-01-06 2017-01-05 Polythérapie comprenant composé de fer et composé de citrate

Publications (1)

Publication Number Publication Date
EP3399970A1 true EP3399970A1 (fr) 2018-11-14

Family

ID=57963442

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17703245.5A Withdrawn EP3399970A1 (fr) 2016-01-06 2017-01-05 Polythérapie comprenant composé de fer et composé de citrate

Country Status (5)

Country Link
EP (1) EP3399970A1 (fr)
JP (1) JP2019501184A (fr)
CN (1) CN108883085A (fr)
CA (1) CA3010771A1 (fr)
WO (1) WO2017120311A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210077451A1 (en) * 2018-01-02 2021-03-18 Kashiv Biosciences, Llc A stable oral pharmaceutical composition of ferric citrate
CN112457350A (zh) * 2020-11-30 2021-03-09 中国大冢制药有限公司 一种枸橼酸焦磷酸铁络合物及其制备方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6689275B1 (en) 1996-12-31 2004-02-10 Ajay Gupta Method and pharmaceutical composition for replacing iron losses in dialysis patients
US6779468B1 (en) 1997-08-07 2004-08-24 Ajay Gupta Method and pharmaceutical composition for iron delivery in hemodialysis and peritoneal dialysis patients
JP4655338B2 (ja) * 2000-07-06 2011-03-23 大正製薬株式会社 鉄欠乏性貧血改善のための薬剤
US7857977B2 (en) 2005-07-12 2010-12-28 Rockwell Medical Technologies, Inc. Packaging of ferric pyrophosphate for dialysis
US7816404B2 (en) 2007-07-20 2010-10-19 Rockwell Medical Technologies, Inc. Methods for the preparation and use of ferric pyrophosphate citrate chelate compositions
US8178709B2 (en) 2009-07-21 2012-05-15 Biolink Life Sciences, Inc. Iron preparation suitable for pharmaceutical formulation and process for the preparation thereof
IN2014DN08761A (fr) * 2012-05-08 2015-05-22 Dsm Ip Assets Bv
EP2842434A1 (fr) * 2013-08-28 2015-03-04 DSM IP Assets B.V. Supplément de fer d'un bouillon concentré

Also Published As

Publication number Publication date
CA3010771A1 (fr) 2017-07-13
CN108883085A (zh) 2018-11-23
WO2017120311A1 (fr) 2017-07-13
JP2019501184A (ja) 2019-01-17

Similar Documents

Publication Publication Date Title
AU706181B2 (en) Composition of cisplatin in combination with 2,2'-dithio-bis(ethanesulfonate) (dimesna)
JP2018138562A (ja) 慢性腎臓病患者の治療におけるクエン酸第二鉄の使用
ES2301142T3 (es) Combinaciones que comprenden inhibidores de dipeptidilpeptidasa-iv y agentes antidiabeticos.
JP6828100B2 (ja) 慢性腎臓病患者の心不全を軽減するためのクエン酸第二鉄
JPH0222229A (ja) 神経細胞及び神経繊維の疾患もしくは傷害の治療に用いる組み合わせ調合剤
RU2541092C2 (ru) Бисглицинат-хелат железа для использования в пероральном лечении анемии у пациентов с целиакией
KR20160105499A (ko) 철 트리말톨의 복용량 양생법
EP3399970A1 (fr) Polythérapie comprenant composé de fer et composé de citrate
CA2965096C (fr) Schema posologique de maltol ferrique
CN116600788A (zh) 盐酸米托蒽醌脂质体的用途
WO2006124573A2 (fr) Traitement du cancer a l'aide de 2-desoxyglucose
JPH11507012A (ja) 心臓血管系病気の処置におけるアンギオテンシン変換酵素阻害薬と副作用軽減量のアルドステロン拮抗薬との組合わせ治療
JP2008524123A (ja) 治療用栄養組成物又は組合せ、及びそれらの使用方法
WO2012156502A2 (fr) Préparation de type bain de bouche à deux composants
CA3234440A1 (fr) Acides 1h-1,2,3-triazole-4-carboxyliques pour le traitement de l'hyperoxalurie et des calculs renaux
RU2188659C1 (ru) Фармацевтическая композиция для терапии человека, обладающая иммунотропным действием
WO2022218958A1 (fr) Combinaison comprenant de l'évérolimus et de l'amcénestrant
US20220175828A1 (en) Liquid concentrates of calcium and magnesium
Sears et al. 2008 new drug approvals
BRAND Mitomycin 20mg/40mg Injection
MXPA97003460A (en) Composition of cisplatine in combination with 2,2'ditio-bis (ethanosulphonate) (dimes)
MX2008004461A (en) Improved toleration iron supplement compositions
WO2009084732A1 (fr) Agent servant à soulager les effets secondaires néfastes d'une thérapie de combinaison interféron/ribavirine

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20180806

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20200801