U.S. patent application number 13/847254 was filed with the patent office on 2013-09-05 for methods and compositions for administration of iron.
This patent application is currently assigned to Luitpold Pharmaceuticals, Inc.. The applicant listed for this patent is LUITPOLD PHARMACEUTICALS, INC.. Invention is credited to Mary Jane Helenek, Richard P. Lawrence, Marc L. Tokars.
Application Number | 20130230565 13/847254 |
Document ID | / |
Family ID | 38233459 |
Filed Date | 2013-09-05 |
United States Patent
Application |
20130230565 |
Kind Code |
A1 |
Helenek; Mary Jane ; et
al. |
September 5, 2013 |
METHODS AND COMPOSITIONS FOR ADMINISTRATION OF IRON
Abstract
The present invention generally relates to treatment of
iron-related conditions with iron carbohydrate complexes. One
aspect of the invention is a method of treatment of iron-related
conditions with a single unit dosage of at least about 0.6 grams of
elemental iron via an iron carbohydrate complex. The method
generally employs iron carbohydrate complexes with nearly neutral
pH, physiological osmolarity, and stable and non-immunogenic
carbohydrate components so as to rapidly administer high single
unit doses of iron intravenously to patients in need thereof.
Inventors: |
Helenek; Mary Jane;
(Brookville, NY) ; Tokars; Marc L.;
(Douglassville, PA) ; Lawrence; Richard P.;
(Calverton, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LUITPOLD PHARMACEUTICALS, INC. |
Shirley |
NY |
US |
|
|
Assignee: |
Luitpold Pharmaceuticals,
Inc.
Shirley
NY
|
Family ID: |
38233459 |
Appl. No.: |
13/847254 |
Filed: |
March 19, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12787283 |
May 25, 2010 |
8431549 |
|
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13847254 |
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11620986 |
Jan 8, 2007 |
7754702 |
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12787283 |
|
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60757119 |
Jan 6, 2006 |
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Current U.S.
Class: |
424/400 ;
514/25 |
Current CPC
Class: |
A61P 35/02 20180101;
A61P 1/00 20180101; A61P 7/06 20180101; A61P 19/02 20180101; A61K
31/721 20130101; A61K 31/7135 20130101; C07H 23/00 20130101; A61P
3/00 20180101; A61P 13/12 20180101; A61K 31/715 20130101; A61P 9/04
20180101; A61P 35/00 20180101 |
Class at
Publication: |
424/400 ;
514/25 |
International
Class: |
C07H 23/00 20060101
C07H023/00 |
Claims
1. A method of treating a disease, disorder, or condition
characterized by iron deficiency or dysfunctional iron metabolism
resulting in reduced bioavailability of dietary iron, comprising
administering to a subject in need thereof an iron carbohydrate
complex in a single dosage unit of at least about 0.6 grams of
elemental iron; wherein the iron carbohydrate complex is selected
from the group consisting of an iron carboxymaltose complex, an
iron mannitol complex, an iron polyisomaltose complex, an iron
polymaltose complex, an iron gluconate complex, an iron sorbitol
complex, and an iron hydrogenated dextran complex.
2. The method of claim 1, wherein the iron carbohydrate complex has
a substantially non-immunogenic carbohydrate component.
3. The method of claim 1, wherein the iron carbohydrate complex has
substantially no cross reactivity with anti-dextran antibodies.
4. The method of claim 1, wherein the disease, disorder, or
condition comprises anemia.
5. The method of claim 4, wherein the anemia comprises iron
deficiency anemia.
6. The method of claim 4, wherein: (i) the anemia comprises an iron
deficiency anemia associated with chronic blood loss; acute blood
loss; pregnancy; childbirth; childhood development; psychomotor and
cognitive development in children; breath holding spells; heavy
uterine bleeding; menstruation; chronic recurrent hemoptysis;
idiopathic pulmonary siderosis; chronic internal bleeding;
gastrointestinal bleeding; parasitic infections; chronic kidney
disease; dialysis; surgery or acute trauma; and chronic ingestion
of alcohol, chronic ingestion of salicylates, chronic ingestion of
steroids; chronic ingestion of non-steroidal anti-inflammatory
agents, or chronic ingestion of erythropoiesis stimulating agents;
(ii) the anemia is of a chronic disease selected from the group
consisting of rheumatoid arthritis; cancer; Hodgkins leukemia;
non-Hodgkins leukemia; cancer chemotherapy; inflammatory bowel
disease; ulcerative colitis thyroiditis; hepatitis; systemic lupus
erythematosus; polymyalgia rheumatica; scleroderma; mixed
connective tissue disease; Sojgren's syndrome; congestive heart
failure/cardiomyopathy; and idiopathic geriatric anemia; (iii) the
anemia is due to impaired iron absorption or poor nutrition; (iv)
the anemia is associated with Crohn's Disease; gastric surgery;
ingestion of drug products that inhibit iron absorption; or chronic
use of calcium.
7. The method of claim 1 wherein the disease, disorder, or
condition is selected from the group consisting of restless leg
syndrome; blood donation; hair loss; and attention deficit
disorder.
8. The method of claim 1 wherein the single dosage unit of
elemental iron is at least about 1.0 grams.
9. The method of claim 1 wherein the single dosage unit of
elemental iron is at least about 1.5 grams.
10. The method of claim 1 wherein the single dosage unit of
elemental iron is at least about 2.0 grams.
11. The method of claim 1 wherein the single dosage unit of
elemental iron is administered in about 15 minutes or less.
12. The method of claim 1 wherein the single dosage unit of
elemental iron is administered in about 5 minutes or less.
13. The method of claim 1 wherein the iron carbohydrate complex is
an iron carboxymaltose complex.
14. The method of claim 13, wherein (i) the iron carboxymaltose
complex has a chemical formula of [FeO.sub.x
(OH).sub.y(H.sub.2O).sub.z].sub.n [{(C.sub.6H.sub.10O.sub.5).sub.m
(C.sub.6H.sub.12O.sub.7)}.sub.l].sub.k, where n is about 103, m is
about 8, l is about 11, and k is about 4; contains about 28%
elemental iron; and has a molecular weight of about 150,000 Da; or
(ii) the iron carboxymaltose complex is a polynuclear iron
(III)-hydroxide
4(R)-(poly-(1.fwdarw.4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-te-
trahydroxy-hexanoate.
15. The method of claim 1, wherein the iron carbohydrate complex is
an iron polyglucose sorbitol carboxymethyl ether complex.
16. The method of claim 15, wherein the iron polyglucose sorbitol
carboxymethyl ether complex is a polyglucose sorbitol carboxymethyl
ether-coated non-stoichiometric magnetite complex.
17. The method of claim 1, wherein mean iron core size is at least
about 1 nm but no greater than about 9 nm; or mean size of a
particle of the iron carbohydrate complex is no greater than about
35 nm.
18. The method of claim 1, wherein the iron carbohydrate complex is
administered parenterally.
19. The method of claim 18, wherein (i) parenteral administration
comprises intravenous infusion and the single unit dose of iron
carbohydrate complex is administered at a concentration of about
1000 mg elemental iron in about 200 ml to about 300 ml of diluent;
(ii) parenteral administration comprises bolus injection and the
single unit dose of iron carbohydrate complex is administered at a
concentration of about 1000 mg elemental iron in about 200 ml to
about 300 ml of diluent; or (iii) parenteral administration
comprises intramuscular injection and the single unit dose of iron
carbohydrate complex is administered at a concentration of about
500 mg elemental iron in less than about 10 ml diluent.
20. The method of claim 1 further comprising a second
administration of said iron carbohydrate complex upon recurrence of
at least one symptom of the disease, disorder, or condition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation application that claims
priority to U.S. Non-Provisional application Ser. No. 12/787,283,
filed 25 May 2010 and U.S. Non-Provisional application Ser. No.
11/620,986, filed 8 Jan. 2007, issued as U.S. Pat. No. 7,754,702 on
13 Jul. 2010, both of which claim priority to U.S. Provisional
Application Ser. No. 60/757,119, filed 6 Jan. 2006, each of which
is incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention generally relates to treatment of
iron-related conditions with iron carbohydrate complexes.
BACKGROUND
[0003] Parenteral iron therapy is known to be effective in a
variety of diseases and conditions including, but not limited to,
severe iron deficiency, iron deficiency anemia, problems of
intestinal iron absorption, intestinal iron intolerance, cases
where regular intake of an oral iron preparation is not guaranteed,
iron deficiency where there is no response to oral therapy (e.g.,
dialysis patients), and situations where iron stores are scarcely
or not at all formed but would be important for further therapy
(e.g., in combination with erythropoietin). Geisser et al.,
Arzneimittelforschung (1992) 42(12), 1439-1452. There exist various
commercially available parenteral iron formulations. But many
currently available parenteral iron drugs, while purportedly
effective at repleting iron stores, have health risks and dosage
limitations associated with their use.
[0004] Currently available parenteral iron formulations approved
for use in the U.S. include iron dextran (e.g., InFed, Dexferrum),
sodium ferric gluconate complex in sucrose (Ferrlecit), and iron
sucrose (Venofer). Although serious and life-threatening reactions
occur most frequently with iron dextran, they are also known to
occur with other parenteral iron products. In addition, non-life
threatening reactions such as arthralgia, back pain, hypotension,
fever, myalgia, pruritus, vertigo, and vomiting also occur. These
reactions, while not life-threatening, often preclude further
dosing and therefore iron repletion.
[0005] Iron dextran, the first parenteral iron product available in
the United States (US), has been associated with an incidence of
anaphylactoid-type reactions (i.e., dyspnea, wheezing, chest pain,
hypotension, urticaria, angioedema). See generally Fishbane, Am J
Kidney Dis (2003) 41(5Suppl), 18-26; Landry et al. (2005) Am J
Nephrol 25, 400-410, 407. This high incidence of anaphylactoid
reactions is believed to be caused by the formation of antibodies
to the dextran moiety. Other parenteral iron products (e.g., iron
sucrose and iron gluconate) do not contain the dextran moiety, and
the incidence of anaphylaxis with these products is markedly lower.
Fishbane, Am J Kidney Dis (2003) 41(5Suppl), 18-26; Geisser et al.,
Arzneimittelforschung (1992) 42(12), 1439-52. However, the physical
characteristics of, for example, iron gluconate and iron sucrose
lead to dosage and administration rate limitations. Negative
characteristics include high pH, high osmolarity, low dosage limits
(e.g., maximum 500 mg iron once per week, not exceeding 7 mg
iron/kg body weight), and the long duration of administration
(e.g., 100 mg iron over at least 5 minutes as an injection; 500 mg
iron over at least 3.5 hours as a drip infusion). Furthermore,
injectable high molecular mass substances produce more allergic
reactions than the corresponding low molecular mass substances.
Geisser et al. (1992) Arzneimittelforschung 42: 1439-1452.
[0006] Ferumoxytol is a newer parenteral iron formulation but
limited information is available as to its efficacy and
administration. See e.g., Landry et al. (2005) Am J Nephrol 25,
400-410, 408; and Spinowitz et al. (2005) Kidney Intl 68,
1801-1807; U.S. Pat. No. 6,599,498.
[0007] Various pharmacokinetic studies suggest that doses of iron
complexes higher than 200 mg of iron are generally unsuitable and
that the conventional therapy model prescribes repeated
applications of lower doses over several days. See Geisser et al.,
(1992) Arzneimittelforschung 42: 1439-1452. For example, to achieve
iron repletion under current therapy models, a total dose of 1 g
typically requires 5 to 10 sessions over an extended period of
time. These delivery modes incur significant expense for supplies
such as tubing and infusate, costly nursing time, multiple
administrations, and patient inconvenience.
SUMMARY OF THE INVENTION
[0008] Among the various aspects of the present invention is the
provision of a method of treatment of iron-associated diseases,
disorders, or conditions with iron formulations. Briefly,
therefore, the present invention is directed to use of iron
carbohydrate complexes that can be administered parenterally at
relatively high single unit dosages, thereby providing a safe and
efficient means for delivery of a total dose of iron in fewer
sessions over the course of therapeutic treatment.
[0009] The present teachings include methods of treating a disease,
disorder, or condition characterized by iron deficiency or
dysfunctional iron metabolism through the administration of at
least 0.6 grams of elemental iron via a single unit dosage of an
iron carbohydrate complex to a subject that is in need of such
therapy.
[0010] In various embodiments, the method treats anemia. In some
embodiments, the anemia is an iron deficiency anemia, such as that
associated with chronic blood loss; acute blood loss; pregnancy;
childbirth; childhood development; psychomotor and cognitive
development in children; breath holding spells; heavy uterine
bleeding; menstruation; chronic recurrent hemoptysis; idiopathic
pulmonary siderosis; chronic internal bleeding; gastrointestinal
bleeding; parasitic infections; chronic kidney disease; dialysis;
surgery or acute trauma; and chronic ingestion of alcohol, chronic
ingestion of salicylates, chronic ingestion of steroids; chronic
ingestion of non-steroidial anti-inflammatory agents, or chronic
ingestion of erythropoiesis stimulating agents. In some aspects,
the anemia is anemia of chronic disease, such as rheumatoid
arthritis; cancer; Hodgkins leukemia; non-Hodgkins leukemia; cancer
chemotherapy; inflammatory bowel disease; ulcerative colitis
thyroiditis; hepatitis; systemic lupus erythematosus; polymyalgia
rheumatica; scleroderma; mixed connective tissue disease; Sojgren's
syndrome; congestive heart failure/cardiomyopathy; or idiopathic
geriatric anemia. In some embodiments, the anemia is due to
impaired iron absorption or poor nutrition, such as anemia
associated with Crohn's Disease; gastric surgery; ingestion of drug
products that inhibit iron absorption; and chronic use of calcium.
In various embodiments, the method treats restless leg syndrome;
blood donation; Parkinson's disease; hair loss; or attention
deficit disorder.
[0011] In various embodiments, the single dosage unit of elemental
iron is between at least about 0.6 grams and 2.5 grams. In some
embodiments, the single dosage unit of elemental iron is at least
about 0.7 grams; at least about 0.8 grams; at least about 0.9
grams; at least about 1.0 grams; at least about 1.1 grams; at least
about 1.2 grams; at least about 1.3 grams; at least about 1.4
grams; at least about 1.5 grams; at least about 1.6 grams; at least
about 1.7 grams; at least about 1.8 grams; at least about 1.9
grams; at least about 2.0 grams; at least about 2.1 grams; at least
about 2.2 grams; at least about 2.3 grams; at least about 2.4
grams; or at least about 2.5 grams.
[0012] In various embodiments, the single dosage unit of elemental
iron is administered in about 15 minutes or less. In some
embodiments, the single dosage unit of elemental iron is
administered in about 10 minutes or less, about 5 minutes or less,
or about 2 minutes or less.
[0013] In various embodiments, the subject does not experience a
significant adverse reaction to the single dosage unit
administration.
[0014] In various embodiments, the iron carbohydrate complex has a
pH between about 5.0 to about 7.0; physiological osmolarity; an
iron core size no greater than about 9 nm; a mean diameter particle
size no greater than about 35 nm; a blood half-life of between
about 10 hours to about 20 hours; a substantially non-immunogenic
carbohydrate component; and substantially no cross reactivity with
anti-dextran antibodies.
[0015] In various embodiments, the iron carbohydrate complex
contains about 24% to about 32% elemental iron; contains about 25%
to about 50% carbohydrate; has a molecular weight of about 90,000
daltons to about 800,000 daltons, or some combination thereof.
[0016] In various embodiments, the iron carbohydrate complex is an
iron monosaccharide complex, an iron disaccharide complex, or an
iron polysaccharide complex. In some embodiments, the iron
carbohydrate complex is iron carboxymaltose complex, iron mannitol
complex, iron polyisomaltose complex, iron polymaltose complex,
iron gluconate complex, iron sorbitol complex, or an iron
hydrogenated dextran complex. In some embodiments, the iron
carbohydrate complex is an iron polyglucose sorbitol carboxymethyl
ether complex. In some preferred embodiments, the iron
carboxymaltose complex contains about 24% to about 32% elemental
iron, about 25% to about 50% carbohydrate, and is about 100,000
daltons to about 350,000 daltons. In some preferred embodiments,
the iron carboxymaltose complex is obtained from an aqueous
solution of iron (III) salt and an aqueous solution of the
oxidation product of one or more maltodextrins using an aqueous
hypochlorite solution at a pH value within the alkaline range,
wherein, when one maltodextrin is applied, its dextrose equivalent
lies between 5 and 20, and when a mixture of several maltodextrins
is applied, the dextrose equivalent lies between 5 and 20 and the
dextrose equivalent of each individual maltodextrin contained in
the mixture lies between 2 and 20. In some preferred embodiments,
the iron carboxymaltose complex has a chemical formula of
[FeO.sub.x(OH).sub.y(H.sub.2O).sub.z].sub.n
[{(C.sub.6H.sub.10O.sub.5).sub.m
(C.sub.6H.sub.12O.sub.7)}.sub.l].sub.k, where n is about 103, m is
about 8, l is about 11, and k is about 4; contains about 28%
elemental iron; and has a molecular weight of about 150,000 Da. In
some preferred embodiments, the iron carboxymaltose complex is
polynuclear iron (III)-hydroxide
4(R)-(poly-(1.fwdarw.4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-te-
trahydroxy-hexanoate.
[0017] In various embodiments, the iron carbohydrate complex
comprises an iron core with a mean iron core size of no greater
than about 9 nm. In some embodiments, the mean iron core size is at
least about 1 nm but no greater than about 9 nm; at least about 3
nm but no greater than about 7 nm; or at least about 4 nm but not
greater than about 5 nm.
[0018] In various embodiments, the mean size of a particle of the
iron carbohydrate complex is no greater than about 35 nm. In some
embodiments, the particle mean size is no greater than about 30 nm.
In some embodiments, the particle mean size is no greater than
about 25 nm. In some embodiments, the particle mean size is no
greater than about 20 nm; no greater than about 15 nm; no greater
than about 10 nm; or at least about 6 nm but no greater than about
7 nm.
[0019] In various embodiments, the iron carbohydrate complex is
administered parenterally, for example intravenously or
intramuscularly. In some embodiments, the iron carbohydrate complex
is intravenously infused. In certain embodiments, the single unit
dose of iron carbohydrate complex is intravenously infused at a
concentration of about 1000 mg elemental iron in about 200 ml to
about 300 ml of diluent, for example, about 250 ml of diluent or
about 215 ml of diluent. In some embodiments, the iron carbohydrate
complex is intravenously injected as a bolus. In certain
embodiments, the iron carbohydrate complex is intravenously
injected as a bolus at a concentration of about 1000 mg elemental
iron in about 200 ml to about 300 ml of diluent, for example, about
250 ml of diluent or about 215 ml of diluent. In some embodiments,
the iron carbohydrate complex is intramuscularly infused at a
concentration of about 1000 mg elemental iron in about 200 ml to
about 300 ml of diluent, for example, about 250 ml of diluent or
about 215 ml of diluent. In some embodiments, the iron carbohydrate
complex is intramuscularly infused at a concentration of about 500
mg elemental iron in less than about 10 ml diluent.
[0020] In various embodiments, the method also includes a second
administration of the iron carbohydrate complex upon recurrence of
at least one symptom of the treated disease, disorder, or
condition.
[0021] In various embodiments, the method also includes a second
administration of the iron carbohydrate complex after 1 day to 12
months after the first administration.
[0022] In a preferred embodiment, the method of treating a disease,
disorder, or condition characterized by iron deficiency or
dysfunctional iron metabolism comprises intravenously administering
to a subject in need thereof an iron carboxymaltose complex in a
single dosage unit of at least about 1000 mg of elemental iron in
about 200 ml to about 300 ml of diluent in about 5 minutes or less;
wherein the iron carboxymaltose complex comprises an iron core with
a mean iron core size of at least about 1 nm but no greater than
about 9 nm; mean size of a particle of the iron carboxymaltose
complex is no greater than about 35 nm; and the iron carboxymaltose
complex is administered intravenously infused or intravenously
injected at a concentration of about 1000 mg elemental iron in
about 200 ml to about 300 ml of diluent. In some these embodiments,
the iron carboxymaltose complex is polynuclear iron (III)-hydroxide
4(R)-(poly-(1.fwdarw.4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-te-
trahydroxy-hexanoate. In some these embodiments, the iron
carboxymaltose complex is obtained from an aqueous solution of iron
(III) salt and an aqueous solution of the oxidation product of one
or more maltodextrins using an aqueous hypochlorite solution at a
pH value within the alkaline range, wherein, when one maltodextrin
is applied, its dextrose equivalent lies between about 5 and about
20, and when a mixture of several maltodextrins is applied, the
dextrose equivalent lies between about 5 and about 20 and the
dextrose equivalent of each individual maltodextrin contained in
the mixture lies between about 2 and about 20.
[0023] Other objects and features will be in part apparent and in
part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Those of skill in the art will understand that the drawings,
described below, are for illustrative purposes only. The drawings
are not intended to limit the scope of the present teachings in any
way.
[0025] FIG. 1 is a series of electron micrographs that depict the
particle size of three iron carbohydrate complexes. FIG. 1A is an
electron micrograph depicting the particle size of Dexferrum (an
iron dextran). FIG. 1B is an electron micrograph depicting the
particle size of Venofer (an iron sucrose). FIG. 1C is an electron
micrograph depicting the particle size of polynuclear iron
(III)-hydroxide
4(R)-(poly-(1.fwdarw.4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-te-
trahydroxy-hexanoate ("VIT-45", an iron carboxymaltose
complex).
[0026] FIG. 2 is a schematic representation of an exemplary iron
carboxymaltose complex.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention makes use of iron carbohydrate
complexes that can be administered parenterally at relatively high
single unit dosages for the therapeutic treatment of a variety of
iron-associated diseases, disorders, or conditions. Generally,
states indicative of a need for therapy with high single unit
dosages of iron carbohydrate complexes include, but are not limited
to iron deficiency anemia, anemia of chronic disease, and states
characterized by dysfunctional iron metabolism. Efficacious
treatment of these, and other, diseases and conditions with
parenteral iron formulations (supplied at lower single unit dosages
than those described herein) is generally known in the art. See
e.g., Van Wyck et al. (2004) J Am Soc Nephrol 15, S91-S92. The
present invention is directed to use of iron carbohydrate complexes
that can be administered parenterally at relatively high single
unit dosages, thereby providing a safe and efficient means for
delivery of a total dose of iron in fewer sessions over the course
of therapeutic treatment.
[0028] Iron deficiency anemia is associated with, for example,
chronic blood loss; acute blood loss; pregnancy; childbirth;
childhood development; psychomotor and cognitive development in
children; breath holding spells; heavy uterine bleeding;
menstruation; chronic recurrent hemoptysis; idiopathic pulmonary
siderosis; chronic internal bleeding; gastrointestinal bleeding;
parasitic infections; chronic kidney disease; dialysis; surgery or
acute trauma; and chronic ingestion of alcohol, chronic ingestion
of salicylates, chronic ingestion of steroids; chronic ingestion of
non-steroidial anti-inflammatory agents, or chronic ingestion of
erythropoiesis stimulating agents.
[0029] Anemia of chronic disease is associated with, for example,
rheumatoid arthritis; cancer; Hodgkins leukemia; non-Hodgkins
leukemia; cancer chemotherapy; inflammatory bowel disease;
ulcerative colitis thyroiditis; hepatitis; systemic lupus
erythematosus; polymyalgia rheumatica; scleroderma; mixed
connective tissue disease; Sojgren's syndrome; congestive heart
failure/cardiomyopathy; and idiopathic geriatric anemia.
[0030] Anemia is also associated with, for example, Crohn's
Disease; gastric surgery; ingestion of drug products that inhibit
iron absorption; and chronic use of calcium.
[0031] States characterized by dysfunctional iron metabolism and
treatable with the single unit dosages of iron carbohydrate
complexes described herein include, but are not limited to,
restless leg syndrome; blood donation; Parkinson's disease; hair
loss; and attention deficit disorder.
[0032] Again, each of the above listed states, diseases, disorders,
and conditions, as well as others, can benefit from the treatment
methodologies described herein. Generally, treating a state,
disease, disorder, or condition includes preventing or delaying the
appearance of clinical symptoms in a mammal that may be afflicted
with or predisposed to the state, disease, disorder, or condition
but does not yet experience or display clinical or subclinical
symptoms thereof. Treating can also include inhibiting the state,
disease, disorder, or condition, e.g., arresting or reducing the
development of the disease or at least one clinical or subclinical
symptom thereof. Furthermore, treating can include relieving the
disease, e.g., causing regression of the state, disease, disorder,
or condition or at least one of its clinical or subclinical
symptoms.
[0033] The benefit to a subject to be treated is either
statistically significant or at least perceptible to the patient or
to the physician. Measures of efficacy of iron replacement therapy
are generally based on measurement of iron-related parameters in
blood. The aim of treatment is usually to return both Hb and iron
stores to normal levels. Thus, efficacy of iron replacement therapy
can be interpreted in terms of the ability to normalise Hb levels
and iron stores. The effectiveness of treatment with one or more
single unit doses of iron carbohydrate complex, as described
herein, can be demonstrated, for example, by improvements in
ferritin and transferrin saturation, and in raising hemoglobin
levels in anemic patients. Iron stores can be assessed by
interpreting serum ferritin levels. TfS is frequently used, in
addition, to diagnose absolute or functional iron deficiencies. In
patients with iron deficiency, serum transferrin is elevated and
will decrease following successful iron treatment.
[0034] Administration
[0035] Methods of treatment of various diseases, disorders, or
conditions with iron complex compositions comprise the
administration of the complex in single unit dosages of at least
0.6 grams of elemental iron to about at least 2.5 grams of
elemental iron. Administration of single unit dosages can be, for
example, over pre-determined time intervals or in response to the
appearance and/or reappearance of symptoms. For example, the iron
carbohydrate complex can be re-administered upon recurrence of at
least one symptom of the disease or disorder. As another example,
the iron carbohydrate complex can be re-administered at some time
period after the initial administration (e.g., after 4 days to 12
months).
[0036] Any route of delivery of the single unit dose of iron
carbohydrate complex is acceptable so long as iron from the iron
complex is released such that symptoms are treated. The single unit
dose of iron carbohydrate complex can be administered parenterally,
for example intravenously or intramuscularly. Intravenous
administration can be delivered as a bolus or preferably as an
infusion. For example, the single unit dose of iron carbohydrate
complex can be intravenously infused at a concentration of about
1000 mg elemental iron in about 200 ml to about 300 ml of diluent,
preferably about 215 ml of diluent or about 250 ml of diluent. The
iron carbohydrate complex can be intravenously injected as a bolus.
For example, the iron carbohydrate complex can be intravenously
injected as a bolus at a concentration of about 1000 mg elemental
iron in about 200 ml to about 300 ml of diluent, preferably about
215 ml of diluent or about 250 ml of diluent. The iron carbohydrate
complex can be intramuscularly infused at a concentration of, for
example, about 1000 mg elemental iron in about 200 ml to about 300
ml of diluent, preferably, about 250 ml of diluent or about 215 ml
of diluent. If applied as an infusion, the iron carbohydrate
complex can be diluted with sterile saline (e.g., polynuclear iron
(III)-hydroxide
4(R)-(poly-(1.fwdarw.4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-te-
trahydroxy-hexanoate ("VIT-45") 0.9% m/V NaCl or 500 mg iron in up
to 250 mL NaCl). The iron carbohydrate complex can be intravenously
injected as a bolus without dilution. As an example, the iron
carbohydrate complex can be intramuscularly injected at a
concentration of about 500 mg elemental iron in less than about 10
ml diluent, preferably about 5 ml.
[0037] Generally, total iron dosage will depend on the iron deficit
of the patient. One skilled in the art can tailor the total iron
dose required for a subject while avoiding iron overload, as
overdosing with respect to the total required amount of iron has to
be avoided, as is the case for all iron preparations.
[0038] The total iron dosage can be delivered as a single unit
dosage or a series of single unit dosages. An appropriate single
unit dosage level will generally be at least 0.6 grams of elemental
iron, particularly at least 0.7 grams; at least 0.8 grams; at least
0.9 grams; at least 1.0 grams; at least 1.1 grams; at least 1.2
grams; at least 1.3 grams; at least 1.4 grams; at least 1.5 grams;
at least 1.6 grams; at least 1.7 grams; at least 1.8 grams; at
least 1.9 grams; at least 2.0 grams; at least 2.1 grams; at least
2.2 grams; at least 2.3 grams; at least 2.4 grams; or at least 2.5
grams. For example, a single unit dosage is at least 1.0 grams of
elemental iron. As another example, a single unit dosage is at
least 1.5 grams of elemental iron. As a further example, a single
unit dosage is at least 2.0 grams of elemental iron. In yet another
example, a single unit dosage is at least 2.5 grams of elemental
iron.
[0039] An appropriate single unit dosage level can also be
determined on the basis of patient weight. For example, an
appropriate single unit dosage level will generally be at least 9
mg of elemental iron per kg body weight, particularly at least 10.5
mg/kg, at least 12 mg/kg, at least 13.5 mg/kg, at least 15 mg/kg,
at least 16.5 mg/kg, at least 18 mg/kg, at least 19.5 mg/kg, at
least 21 mg/kg, at least 22.5 mg/kg, at least 24 mg/kg, at least
25.5 mg/kg, at least 27 mg/kg, at least 28.5 mg/kg, at least 30
mg/kg, at least 31.5 mg/kg, at least 33 mg/kg, at least 34.5 mg/kg,
at least 36 mg/kg, or at least 37.5 mg/kg.
[0040] Preferably, a single unit dosage can be administered in 15
minutes or less. For example, the single unit dosage can be
administered in 14 minutes or less, 13 minutes or less, 12 minutes
or less, 11 minutes or less, 10 minutes or less, 9 minutes or less,
8 minutes or less, 7 minutes or less, 6 minutes or less, 5 minutes
or less, 4 minutes or less, 3 minutes or less, or 2 minutes or
less.
[0041] Administration of iron can occur as a one-time delivery of a
single unit dose or over a course of treatment involving delivery
of multiple single unit doses. Multiple single unit doses can be
administered, for example, over pre-determined time intervals or in
response to the appearance and reappearance of symptoms. The
frequency of dosing depends on the disease or disorder being
treated, the response of each individual patient, and the
administered amount of elemental iron. An appropriate regime of
dosing adequate to allow the body to absorb the iron from the
bloodstream can be, for example, a course of therapy once every day
to once every eighteen months.
[0042] Such consecutive single unit dosing can be designed to
deliver a relatively high total dosage of iron over a relatively
low period of time. For example, a single unit dose (e.g., 1000 mg)
can be administered every 24 hours. As illustration, a total dose
of 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg of elemental iron
can be delivered via consecutive daily single unit doses of about
600 mg to about 1000 mg of elemental iron. Given that a single unit
dose of 1000 mg can be intravenously introduced into a patient in a
concentrated form over, for example, two minutes, such
administrative protocol provides a practitioner and patient with an
effective, efficient, and safe means to deliver elemental iron.
[0043] As another example, a single unit dose can be administered
every 3-4 days. As a further example, a single unit dose can be
administered once per week. Alternatively, the single unit doses of
iron complex may be administered ad hoc, that is, as symptoms
reappear, as long as safety precautions are regarded as practiced
by medical professionals.
[0044] It will be understood, however, that the specific dose and
frequency of administration for any particular patient may be
varied and depends upon a variety of factors, including the
activity of the employed iron complex, the metabolic stability and
length of action of that complex, the age, body weight, general
health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity and nature of the
particular condition, and the host undergoing therapy.
[0045] The following provides but a few examples of treatment
protocols for various diseases or disorders.
[0046] Iron carbohydrate complex can be given as a single unit dose
for the treatment of Restless Leg Syndrome. For example, 1000 mg of
elemental iron from an iron carboxymaltose (e.g., polynuclear iron
(III)-hydroxide
4(R)-(poly-(1.fwdarw.4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-te-
trahydroxy-hexanoate) can be intravenously injected as a single
dose (e.g., 1.5-5 mg iron/ml in normal saline) to a subject
suffering from Restless Leg Syndrome. A single intravenous
treatment can provide relief of symptoms for an extended period of
time, approximately two to twelve months, although relief may be
granted for shorter or longer periods. See U.S. Patent Pub. No.
2004/0180849, incorporated herein by reference. If desired,
post-infusion changes in central nervous system iron status can be
monitored using measurements of cerebral spinal fluid (CSF)
ferritin (and other iron-related proteins) and of brain iron stores
using MRI. Post-infusion changes in Restless Leg Syndrome are
assessed using standard subjective (e.g., patient diary, rating
scale) and objective (e.g., P50, SIT, Leg Activity Meters) measures
of clinical status. If desired, to better evaluate RLS symptom
amelioration, CSF and serum iron values, MRI measures of brain iron
and full clinical evaluations with sleep and immobilization tests
are obtained prior to treatment, approximately two weeks after
treatment, and again twelve months later or when symptoms return.
Clinical ratings, Leg Activity Meter recordings and serum ferritin
are obtained monthly after treatment. CSF ferritin changes can also
be used to assess symptom dissipation.
[0047] Iron carbohydrate complex can be given as a single unit dose
for the treatment of iron deficiency anemia secondary to heavy
uterine bleeding. For example, a single unit dose of 1,000 mg of
elemental iron from an iron carboxymaltose in about 250 cc normal
saline can be intravenously injected into a subject suffering from
iron deficiency anemia secondary to heavy uterine bleeding over 15
minutes every week until a calculated iron deficit dose has been
administered. The iron deficit dose can be calculated as
follows:
If baseline TSAT <20% or Baseline Ferritin <50 ng/ml:
Dose=Baseline weight (kg).times.(15-Baseline Hgb
[g/dL]).times.2.4+500 mg
OR
If baseline TSAT >20% and Baseline Ferritin >50 ng/mL:
Dose=Baseline weight (kg).times.(15-Baseline Hgb [g/dL]).times.2.4
[0048] (NOTE: Baseline Hgb equals the average of the last two
central lab Hgb's)
[0049] Iron carbohydrate complex can be given as a single unit dose
for the treatment of iron deficiency anemia. A subject diagnosed as
suffering from iron deficiency anemia can be, for example,
intravenously injected with a dose of 1,000 mg of iron as VIT-45
(or 15 mg/kg for weight <66 kg) in 250 cc of normal saline over
15 minutes. Subjects with iron deficiency anemia secondary to
dialysis or non-dialysis dependent-Chronic Kidney Disease (CKD) as
per K/DOQI guidelines will generally have Hgb <12 g/dL; TSAT
<25%; and Ferritin <300 ng/mL. Subjects with iron deficiency
anemia secondary to Inflammatory Bowel Disease will generally have
Hgb <12 g/dL; TSAT <25%; and Ferritin <300 ng/mL. Subjects
with iron deficiency anemia secondary to other conditions will
generally have Hgb <12 g/dL; TSAT <25%; and Ferritin <100
ng/mL.
[0050] Subject in Need Thereof
[0051] Single unit dosages of intravenous iron described herein can
be administered to a subject where there is a clinical need to
deliver iron rapidly or in higher doses and/or in subjects with
functional iron deficiency such as those on erythropoietin therapy.
A determination of the need for treatment with parenteral iron is
within the abilities of one skilled in the art. For example, need
can be assessed by monitoring a patient's iron status. The
diagnosis of iron deficiency can be based on appropriate laboratory
tests, for example, haemoglobin (Hb), serum ferritin, serum iron,
transferrin saturation (TfS), and hypochromic red cells.
[0052] A determination of the need for treatment with high dosages
of parenteral iron can be also be determined through diagnosis of a
patient as suffering from a disease, disorder, or condition that is
associated with iron deficiency or dysfunctional iron metabolism.
For example, many chronic renal failure patients receiving
erythropoietin will require intravenous iron to maintain target
iron levels. As another example, most hemodialysis patients will
require repeated intravenous iron administration, due to
dialysis-associated blood loss and resulting negative iron
balance.
[0053] Monitoring frequency can depend upon the disease, disorder,
or condition the patient is afflicted with or at risk for. For
example, in a patient initiating erythropoietin therapy, iron
indices are monitored monthly. As another example, in patients who
have achieved target range Hb or are receiving intravenous iron
therapy, TSAT and ferritin levels can be monitored every 3
months.
[0054] A patient's iron status can be indicative of an absolute or
a functional iron deficiency, both of which can be treated with the
compositions and methods described herein. An absolute iron
deficiency occurs when an insufficient amount of iron is available
to meet the body's requirements. The insufficiency may be due to
inadequate iron intake, reduced bioavailability of dietary iron,
increased utilization of iron, or chronic blood loss. Prolonged
iron deficiency can lead to iron deficiency anemia--a microcytic,
hypochromic anemia in which there are inadequate iron stores.
Absolute iron deficiency is generally indicated where TSAT <20%
and Ferritin <100 ng/mL.
[0055] Functional iron deficiency can occur where there is a
failure to release iron rapidly enough to keep pace with the
demands of the bone marrow for erythropoiesis, despite adequate
total body iron stores. In these cases, ferritin levels may be
normal or high, but the supply of iron to the erythron is limited,
as shown by a low transferrin saturation and an increased number of
microcytic, hypochromic erythrocytes. Functional iron deficiency
can be characterized by the following characteristics: Inadequate
hemoglobin response to erythropoietin; Serum ferritin may be normal
or high; Transferrin saturation (TSAT) usually <20%; and/or
reduced mean corpuscular volume (MCV) or mean corpuscular
hemoglobin concentration (MCHC) in severe cases. Functional iron
deficiency (i.e., iron stores are thought to be adequate but
unavailable for iron delivery) is generally indicated where TSAT
<20% and Ferritin >100 ng/mL.
[0056] Assessing the need for intravenous iron therapy as described
herein can be according to the National Kidney Foundation's Kidney
Disease Outcomes Quality Initiative. See NKF-K/DOQI, Clinical
Practice Guidelines for Anemia of Chronic Kidney Disease (2000); Am
J Kidney Dis (2001) 37(supp 1), S182-S238. The DOQI provides
optimal clinical practices for the treatment of anemia in chronic
renal failure. The DOQI guidelines specify intravenous iron
treatment of kidney disease based on hemoglobin, transferrin
saturation (TSAT), and ferritin levels.
[0057] Assessment of need for intravenous iron therapy can also be
according to a patient's target iron level. For example, the target
hemoglobin level of a patient can be selected as 11.0 g/dL to 12.0
g/dL (hematocrit approximately 33% to 36%). To achieve target
hemoglobin with optimum erythropoietin doses, sufficient iron,
supplied via an iron carbohydrate complex, is provided to maintain
TSAT .gtoreq.20% and ferritin .gtoreq.100 ng/mL. In
erythropoietin-treated patients, if TSAT levels are below 20%, the
likelihood that hemoglobin will rise or erythropoietin doses fall
after iron administration is high. Achievement of target hemoglobin
levels with optimum erythropoietin doses is associated with
providing sufficient iron to maintain TSAT above 20%.
[0058] Iron therapy can be given to maintain target hemoglobin
while preventing iron deficiency and also preventing iron overload.
Adjusting dosage of iron to maintain target levels of hemoglobin,
hematocrit, and laboratory parameters of iron storage is within the
normal skill in the art. For example, where a patient is anemic or
iron deficient, intravenous iron can be administered when a patient
has a ferritin <800, a TSAT<50, and/or a Hemoglobin <12.
Iron overload can be avoided by withholding iron for TSAT >50%
and/or ferritin >800 ng/mL.
[0059] Where a patient is not anemic or iron deficient but is in
need of iron administration, for example a patient suffering from
Restless Leg Syndrome, hemoglobin and TSAT levels are not
necessarily relevant, while ferritin >800 can still provides a
general cut off point for administration.
[0060] Iron Carbohydrate Complex
[0061] Iron carbohydrate complexes are commercially available, or
have well known syntheses. Examples of iron carbohydrate complexes
include iron monosaccharide complexes, iron disaccharide complexes,
iron oligosaccharide complexes, and iron polysaccharide complexes,
such as: iron carboxymaltose, iron sucrose, iron polyisomaltose
(iron dextran), iron polymaltose (iron dextrin), iron gluconate,
iron sorbitol, iron hydrogenated dextran, which may be further
complexed with other compounds, such as sorbitol, citric acid and
gluconic acid (for example iron dextrin-sorbitol-citric acid
complex and iron sucrose-gluconic acid complex), and mixtures
thereof.
[0062] Applicants have discovered that certain characteristics of
iron carbohydrate complexes make them amenable to administration at
dosages far higher than contemplated by current administration
protocols. Preferably, iron carbohydrate complexes for use in the
methods described herein are those which have one or more of the
following characteristics: a nearly neutral pH (e.g., about 5 to
about 7); physiological osmolarity; stable carbohydrate component;
an iron core size no greater than about 9 nm; mean diameter
particle size no greater than about 35 nm, preferably about 25 nm
to about 30 nm; slow and competitive delivery of the complexed iron
to endogenous iron binding sites; serum half-life of over about 7
hours; low toxicity; non-immunogenic carbohydrate component; no
cross reactivity with anti-dextran antibodies; and/or low risk of
anaphylactoid/hypersensitivity reactions.
[0063] It is within the skill of the art to test various
characteristics of iron carbohydrate complexes as so determine
amenability to use in the methods described herein. For example, pH
and osmolarity are straightforward determinations performed on a
sample formulation. Likewise, techniques such as electron
micrograph imaging, transmission electron microscopy, and atomic
force microscopy provide direct methods to analyze both iron core
and particle size. See e.g., FIG. 1; Table 1. The stability of the
carbohydrate complex can be assessed through physicochemical
properties such as kinetic characteristics, thermodynamic
characteristics, and degradation kinetics. See Geisser et al.,
Arzneimittelforschung (1992) 42(12), 1439-1452. Useful techniques
to assess physical and electronic properties include absorption
spectroscopy, X-ray diffraction analysis, transmission electron
microscopy, atomic force microscopy, and elemental analysis. See
Kudasheva et al. (2004) J Inorg Biochem 98, 1757-1769.
Pharmacokinetics can be assessed, for example, by iron tracer
experiments. Hypersensitivity reactions can be monitored and
assessed as described in, for example, Bailie et al. (2005) Nephrol
Dial Transplant, 20(7), 1443-1449. Safety, efficacy, and toxicity
in human subjects can be assessed, for example, as described in
Spinowitz et al. (2005) Kidney Intl 68, 1801-1807.
[0064] A particularly preferred iron carbohydrate complex will have
a pH between 5.0-7.0; physiological osmolarity; an iron core size
no greater than 9 nm; mean diameter particle size no greater than
30 nm; serum half-life of over 10 hours; a non-immunogenic
carbohydrate component; and no cross reactivity with anti-dextran
antibodies. One example of a preferred iron carbohydrate complex
for use in the methods described herein is an iron carboxy-maltose
complex (e.g., polynuclear iron (III)-hydroxide
4(R)-(poly-(1.fwdarw.4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-te-
trahydroxy-hexanoate, "VIT-45"). Another example of a preferred
iron carbohydrate complex for use in the methods described herein
is a carboxyalkylated reduced polysaccharide iron oxide complex
(e.g., ferumoxytol, described in U.S. Pat. No. 6,599,498).
[0065] Preferably, an iron carbohydrate complex, for use in methods
disclosed herein, contains about 24% to about 32% elemental iron,
more preferably about 28% elemental iron. Preferably, an iron
carbohydrate complex, for use in methods disclosed herein, contains
about 25% to about 50% carbohydrate (e.g., total glucose).
Preferably, an iron carbohydrate complex, for use in methods
disclosed herein, is about 90,000 daltons to about 800,000 daltons,
more preferably 100,000 daltons to about 350,000 daltons.
[0066] Iron Carboxymaltose Complex
[0067] One preferred iron carbohydrate complex for use in the
methods described herein is an iron carboxymaltose complex. An
example of an iron carboxymaltose complex is polynuclear iron
(III)-hydroxide
4(R)-(poly-(1-4)-O-.alpha.-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydr-
oxy-hexanoate ("VIT-45"). VIT-45 is a Type I polynuclear iron (III)
hydroxide carbohydrate complex that can be administered as
parenteral iron replacement therapy for the treatment of various
anemia-related conditions as well as other iron-metabolism related
conditions. VIT-45 can be represented by the chemical formula:
[FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}l]k, where n is about
103, m is about 8, l is about 11, and k is about 4). The molecular
weight of VIT-45 is about 150,000 Da. An exemplary depiction of
VIT-45 is provided in FIG. 2.
[0068] The degradation rate and physicochemical characteristics of
the iron carbohydrate complex (e.g., VIT-45) make it an efficient
means of parenteral iron delivery to the body stores. It is more
efficient and less toxic than the lower molecular weight complexes
such as iron sorbitol/citrate complex, and does not have the same
limitations of high pH and osmolarity that leads to dosage and
administration rate limitations in the case of, for example, iron
sucrose and iron gluconate.
[0069] The iron carboxymaltose complex (e.g., VIT-45) generally
does not contain dextran and does not react with dextran
antibodies; therefore, the risk of anaphylactoid/hypersensitivity
reactions is very low compared to iron dextran. The iron
carboxymaltose complex (e.g., VIT-45) has a nearly neutral pH (5.0
to 7.0) and physiological osmolarity, which makes it possible to
administer higher single unit doses over shorter time periods than
other iron-carbohydrate complexes. The iron carboxymaltose complex
(e.g., VIT-45) can mimic physiologically occurring ferritin. The
carbohydrate moiety of iron carboxymaltose complex (e.g., VIT-45)
is metabolized by the glycolytic pathway. Like iron dextran, the
iron carboxymaltose complex (e.g., VIT-45) is more stable than iron
gluconate and sucrose. The iron carboxymaltose complex (e.g.,
VIT-45) produces a slow and competitive delivery of the complexed
iron to endogenous iron binding sites resulting in an acute
toxicity one-fifth that of iron sucrose. These characteristics of
the iron carboxymaltose complex (e.g., VIT-45) allow administration
of higher single unit doses over shorter periods of time than, for
example, iron gluconate or iron sucrose. Higher single unit doses
can result in the need for fewer injections to replete iron stores,
and consequently is often better suited for outpatient use.
[0070] After intravenous administration, the iron carboxymaltose
complex (e.g., VIT-45) is mainly found in the liver, spleen, and
bone marrow. Pharmacokinetic studies using positron emission
tomography have demonstrated a fast initial elimination of
radioactively labeled iron (Fe) .sup.52Fe/.sup.59Fe VIT-45 from the
blood, with rapid transfer to the bone marrow and rapid deposition
in the liver and spleen. See e.g., Beshara et al. (2003) Br J
Haematol 2003; 120(5): 853-859. Eight hours after administration, 5
to 20% of the injected amount was observed to be still in the
blood, compared with 2 to 13% for iron sucrose. The projected
calculated terminal half-life (t.sub.1/2) was approximately 16
hours, compared to 3 to 4 days for iron dextran and 6 hours for
iron sucrose.
[0071] The iron in the iron carboxymaltose complex (e.g., VIT-45)
slowly dissociates from the complex and can be efficiently used in
the bone marrow for Hgb synthesis. Under VIT-45 administration, red
cell utilization, followed for 4 weeks, ranged from 61% to 99%.
Despite the relatively higher uptake by the bone marrow, there was
no saturation of marrow transport systems. Thus, high red cell
utilization of iron carboxymaltose complex occurs in anemic
patients. In addition, the reticuloendothelial uptake of this
complex reflects the safety of polysaccharide complexes.
Non-saturation of transport systems to the bone marrow indicated
the presence of a large interstitial transport pool (e.g.,
transferrin).
[0072] Other studies in patients with iron deficiency anemia
revealed increases in exposure roughly proportional with VIT-45
dose (maximal total serum iron concentration was approximately 150
.mu.g/mL and 320 .mu.g/mL following 500 mg and 1000 mg doses,
respectively). In these studies, VIT-45 demonstrated a
monoexponential elimination pattern with a t.sub.1/2 in the range 7
to 18 hours, with negligible renal elimination.
[0073] Single-dose toxicity studies have demonstrated safety and
tolerance in rodents and dogs of intravenous doses of an iron
carboxymaltose complex (VIT-45) up to 60 times more than the
equivalent of an intravenous infusion of 1,000 mg iron once weekly
in humans. Pre-clinical studies in dogs and rats administered
VIT-45 in cumulative doses up to 117 mg iron/kg body weight over 13
weeks showed no observed adverse effect level in dose-related
clinical signs of iron accumulation in the liver, spleen, and
kidneys. No treatment-related local tissue irritation was observed
in intra-arterial, perivenous, or intravenous tolerance studies in
the rabbit. In vitro and in vivo mutagenicity tests provided no
evidence that VIT-45 is clastogenic, mutagenic, or causes
chromosomal damage or bone marrow cell toxicity. There were no
specific responses to VIT-45 in a dextran antigenicity test.
[0074] Approximately 1700 subjects have been treated with an iron
carboxymaltose complex (VIT-45) in open label clinical trials (see
e.g., Example 5). Many of these subjects have received at least one
dose of 15 mg/kg (up to a maximum dose of 1,000 mg) of VIT-45 over
15 minutes intravenously. Few adverse events and no serious adverse
events or withdrawals due to adverse events related to VIT-45
administration have been reported. No clinically relevant adverse
changes in safety laboratories have been seen.
[0075] The physicochemical characteristics of the iron
carboxymaltose complex (e.g., VIT-45), the pattern of iron
deposition, and the results of the above described studies
demonstrate that iron carboxymaltose complex can be safely
administered at high single unit therapeutic doses as described
herein.
[0076] Polyglucose Sorbitol Carboxymethyl Ether-Coated
Non-Stoichiometric Magnetite
[0077] Another preferred iron carbohydrate complex for use in the
methods described herein is a polyglucose sorbitol carboxymethyl
ether-coated non-stoichiometric magnetite (e.g., "ferumoxytol").
Ferumoxytol is known in the art to be effective for treating anemia
(at single unit doses lower than described herein). See e.g.,
Spinowitz et al. (2005) Kidney Intl 68, 1801-1807. Ferumoxytol is a
superparamagnetic iron oxide that is coated with a low molecular
weight semi-synthetic carbohydrate, polyglucose sorbitol
carboxymethyl ether. Ferumoxytol and its synthesis are described in
U.S. Pat. No. 6,599,498, incorporated herein by reference. Safety,
efficacy, and pharmacokinetics of ferumoxytol are as described, for
example, in Landry et al. (2005) Am J Nephrol 25, 400-410, 408; and
Spinowitz et al. (2005) Kidney Intl 68, 1801-1807.
[0078] The iron oxide of ferumoxytol is a superparamagnetic form of
non-stoichiometric magnetite with a crystal size of 6.2 to 7.3 nm.
Average colloidal particle size can be about 30 nm, as determined
by light scattering. Molecular weight is approximately 750 kD. The
osmolarity of ferumoxytol is isotonic at 297 mOsm/kg and the pH is
neutral. The blood half-life of ferumoxytol is approximately 10-14
hours. It has been previously reported that ferumoxytol can be
given by direct intravenous push over 1-5 minutes in doses up to
1,800 mg elemental iron per minute, with maximal total dose up to
420 mg per injection. Landry et al. (2005) Am J Nephrol 25,
400-410, 408.
[0079] Core and Particle Size
[0080] Intravenous iron agents are generally spheroidal
iron-carbohydrate nanoparticles. At the core of each particle is an
iron-oxyhydroxide gel. The core is surrounded by a shell of
carbohydrate that stabilizes the iron-oxyhydroxide, slows the
release of bioactive iron, and maintains the resulting particles in
colloidal suspension. Iron agents generally share the same core
chemistry but differ from each other by the size of the core and
the identity and the density of the surrounding carbohydrate. See
Table 1; FIG. 1.
TABLE-US-00001 TABLE 1 Core and Particle Size of Iron Carbohydrate
Complexes Iron (III) Control Release Size of the Particle Test (nm)
+/- SEM T.sub.75 (min) Iron core Total Particle Dexferrum (an iron
dextran) 122.5 11.8 .+-. 4 27 .+-. 6 VIT-45 (an iron 117.8 4.4 .+-.
1.4 6.7 .+-. 2.5 carboxymaltose) Venofer (an iron sucrose) 10.2 2.8
.+-. 1 6.5 .+-. 4
[0081] Differences in core size and carbohydrate chemistry can
determine pharmacological and biological differences, including
clearance rate after injection, iron release rate in vitro, early
evidence of iron bioactivity in vivo, and maximum tolerated dose
and rate of infusion.
[0082] One of the primary determinants of iron bioactivity is the
size of the core and the surface area to volume ratio. Generally,
the rate of labile iron release in each agent is inversely related
to the size of its iron core. Van Wyck (2004) J. Am. Soc.
Nephrology 15, S107-S111, S109. Furthermore, in vitro iron donation
to transferrin is inversely related to core size. Core size can
depend upon the number of iron atoms contained within. For example,
the number of iron atoms contained within a 1 nm core is calculated
to be 13, while a 10 nm core is calculated to contain 12770 iron
atoms. Where agents share the same core chemistry, the rate of iron
release per unit surface area is likely similar, differing perhaps
by the strength of the carbohydrate ligand-core iron bound. But for
the same total amount of core iron, surface area available for iron
release increases dramatically as core radius decreases. That is to
say, for equal amounts of iron, the smaller the core, the greater
the surface area available for iron release. Of course, the
explanation for this non-linear trend is the fact that volume is
radius cubed. In short, a collection of many small spheres exposes
a greater total surface area than does a collection of an equal
mass of fewer, larger spheres.
[0083] A smaller iron core size of an iron complex administered for
the treatment of various diseases, disorders, or conditions allows
wider distribution through tissues, a greater rate of labile iron
release, and increased in vitro iron donation to transferrin.
Furthermore, the iron complex is more evenly distributed and
metabolizes faster due to the smaller core size. But if the core
size is too small, the iron complex can move into cells unable to
metabolize iron. In one embodiment, an iron complex with a mean
iron core size of no greater than about 9 nm is administered. In
various embodiments, mean iron core size is less than about 9 nm
but greater than about 1 nm, about 2 nm, about 3 nm, about 4 nm,
about 5 nm, about 6 nm, about 7 nm, or about 8 nm. Mean iron core
size can be, for example, between about 1 nm and about 9 nm;
between about 3 nm and about 7 nm; or between about 4 nm and about
5 nm.
[0084] The molecular weight (i.e., the whole molecular weight of
the agent) is considered a primary determinant in the
pharmacokinetics, or in other words, how quickly it is cleared from
the blood stream. The amount of labile (i.e., biologicaly
available) iron is inversely correlated with the molecular weight
of the iron-carbohydrate complex. Van Wyck (2004) J. Am. Soc.
Nephrology 15, S107-S111, S109. That is to say, the magnitude of
labile iron effect is greatest in iron-carbohydrate compounds of
lowest molecular weight and least in those of the highest molecular
weight. Generally, there is a direct relationship between the
molecular weight of the agent and the mean diameter of the entire
particle (i.e., the iron core along with the carbohydrate shell).
In various embodiments, the mean diameter size of a particle of the
iron carbohydrate complex is no greater than about 35 nm. For
example, the particle mean size can be no greater than about 30 nm.
As another example, the particle mean size can be no greater than
about 25 nm. As another example, the particle mean size can be no
greater than about 20 nm. As another example, the particle mean
size can be no greater than about 15 nm. As a further example, the
particle mean size can be no greater than about 10 nm. As another
example, the particle mean size can be no greater than about 7
nm.
[0085] Absence of Significant Adverse Reaction to the Single Dosage
Unit Administration
[0086] Generally, a safe and effective amount of an iron
carbohydrate complex is, for example, that amount that would cause
the desired therapeutic effect in a patient while minimizing
undesired side effects. The dosage regimen will be determined by
skilled clinicians, based on factors such as the exact nature of
the condition being treated, the severity of the condition, the age
and general physical condition of the patient, and so on.
Generally, treatment-emergent adverse events will occur in less
than about 5% of treated patients. For example, treatment-emergent
adverse events will occur in less than 4% or 3% of treated
patients. Preferably, treatment-emergent adverse events will occur
in less than about 2% of treated patients.
[0087] For example, minimized undesirable side effects can include
those related to hypersensitivity reactions, sometimes classified
as sudden onset closely related to the time of dosing, including
hypotension, bronchospasm, layngospasm, angioedema or uticaria or
several of these together. Hypersensitivity reactions are reported
with all current intravenous iron products independent of dose. See
generally Bailie et al. (2005) Nephrol Dial Transplant, 20(7),
1443-1449. As another example, minimized undesirable side effects
can include those related to labile iron reactions, sometimes
classified as nausea, vomiting, cramps, back pain, chest pain,
and/or hypotension. Labile iron reactions are more common with iron
sucrose, iron gluconate, and iron dextran when doses are large and
given fast.
[0088] Pharmaceutical Formulations
[0089] In many cases, a single unit dose of iron carbohydrate
complex may be delivered as a simple composition comprising the
iron complex and the buffer in which it is dissolved. However,
other products may be added, if desired, for example, to maximize
iron delivery, preservation, or to optimize a particular method of
delivery.
[0090] A "pharmaceutically acceptable carrier" includes any and all
solvents, dispersion media, coatings, antibacterial and anti-fungal
agents, isotonic and absorption delaying agents, and the like,
compatible with pharmaceutical administration (see e.g., Banker,
Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences, 4th
ed. (2002) ISBN 0824706749; Remington The Science and Practice of
Pharmacy, 21st ed. (2005) ISBN 0781746736). Preferred examples of
such carriers or diluents include, but are not limited to, water,
saline, Finger's solutions and dextrose solution. Supplementary
active compounds can also be incorporated into the compositions.
For intravenous administration, the iron carbohydrate complex is
preferably diluted in normal saline to approximately 2-5 mg/ml. The
volume of the pharmaceutical solution is based on the safe volume
for the individual patient, as determined by a medical
professional.
[0091] An iron complex composition of the invention for
administration is formulated to be compatible with the intended
route of administration, such as intravenous injection. Solutions
and suspensions used for parenteral, intradermal or subcutaneous
application can include a sterile diluent, such as water for
injection, saline solution, polyethylene glycols, glycerine,
propylene glycol or other synthetic solvents; antibacterial agents
such as benzyl alcohol or methyl parabens; antioxidants such as
ascorbic acid or sodium bisulfite; buffers such as acetates,
citrates or phosphates, and agents for the adjustment of tonicity
such as sodium chloride or dextrose. The pH can be adjusted with
acids or bases, such as hydrochloric acid or sodium hydroxide.
Preparations can be enclosed in ampules, disposable syringes or
multiple dose vials made of glass or plastic.
[0092] Pharmaceutical compositions suitable for injection include
sterile aqueous solutions or dispersions for the extemporaneous
preparation of sterile injectable solutions or dispersion. For
intravenous administration, suitable carriers include physiological
saline, bacteriostatic water, Cremophor EL.TM. (BASF; Parsippany,
N.J.) or phosphate buffered saline (PBS). The composition must be
sterile and should be fluid so as to be administered using a
syringe. Such compositions should be stable during manufacture and
storage and must be preserved against contamination from
microorganisms, such as bacteria and fungi. The carrier can be a
dispersion medium containing, for example, water, polyol (such as
glycerol, propylene glycol, and liquid polyethylene glycol), and
other compatible, suitable mixtures. Various antibacterial and
anti-fungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, and thimerosal, can contain microorganism
contamination. Isotonic agents such as sugars, polyalcohols, such
as manitol, sorbitol, and sodium chloride can be included in the
composition. Compositions that can delay absorption include agents
such as aluminum monostearate and gelatin.
[0093] Sterile injectable solutions can be prepared by
incorporating an iron complex in the required amount in an
appropriate solvent with a single or combination of ingredients as
required, followed by sterilization. Methods of preparation of
sterile solids for the preparation of sterile injectable solutions
include vacuum drying and freeze-drying to yield a solid containing
the iron complex and any other desired ingredient.
[0094] Active compounds may be prepared with carriers that protect
the compound against rapid elimination from the body, such as a
controlled release formulation, including implants and
microencapsulated delivery systems. Biodegradable or biocompatible
polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Such materials can be obtained commercially from
ALZA Corporation (Mountain View, Calif.) and NOVA Pharmaceuticals,
Inc. (Lake Elsinore, Calif.), or prepared by one of skill in the
art.
[0095] A single unit dose of iron carbohydrate complex may be
intravenously administered in a volume of pharmaceutically
acceptable carrier of, for example, about 1000 mg of elemental iron
in about 200 ml to about 300 ml of diluent. For example, a single
unit dose of iron carbohydrate complex may be intravenously
administered in a volume of pharmaceutically acceptable carrier of
about 1000 mg of elemental iron in about 250 ml of diluent. As
another example, a single unit dose of iron carbohydrate complex
may be intravenously administered in a volume of pharmaceutically
acceptable carrier of about 1000 mg of elemental iron in about 215
ml of diluent.
[0096] A preferred pharmaceutical composition for use in the
methods described herein contains VIT-45 as the active
pharmaceutical ingredient (API) with about 28% weight to weight
(m/m) of iron, equivalent to about 53% m/m iron (III)-hydroxide,
about 37% m/m of ligand, .gtoreq.6% m/m of NaCl, and .ltoreq.10%
m/m of water.
[0097] Kits for Pharmaceutical Compositions
[0098] Iron complex compositions can be included in a kit,
container, pack or dispenser, together with instructions for
administration according to the methods described herein. When the
invention is supplied as a kit, the different components of the
composition may be packaged in separate containers, such as ampules
or vials, and admixed immediately before use. Such packaging of the
components separately may permit long-term storage without losing
the activity of the components. Kits may also include reagents in
separate containers that facilitate the execution of a specific
test, such as diagnostic tests.
[0099] The reagents included in kits can be supplied in containers
of any sort such that the life of the different components are
preserved and are not adsorbed or altered by the materials of the
container. For example, sealed glass ampules or vials may contain
lyophilized iron complex or buffer that have been packaged under a
neutral non-reacting gas, such as nitrogen. Ampules may consist of
any suitable material, such as glass, organic polymers, such as
polycarbonate, polystyrene, etc., ceramic, metal or any other
material typically employed to hold reagents. Other examples of
suitable containers include bottles that are fabricated from
similar substances as ampules, and envelopes that consist of
foil-lined interiors, such as aluminum or an alloy. Other
containers include test tubes, vials, flasks, bottles, syringes,
etc. Containers may have a sterile access port, such as a bottle
having a stopper that can be pierced by a hypodermic injection
needle. Other containers may have two compartments that are
separated by a readily removable membrane that, upon removal,
permits the components to mix. Removable membranes may be glass,
plastic, rubber, etc.
[0100] Kits may also be supplied with instructional materials.
Instructions may be printed on paper or other substrate, and/or may
be supplied on an electronic-readable medium, such as a floppy
disc, CD-ROM, DVD-ROM, mini-disc, SACD, Zip disc, videotape, audio
tape, etc. Detailed instructions may not be physically associated
with the kit; instead, a user may be directed to an internet web
site specified by the manufacturer or distributor of the kit, or
supplied as electronic mail.
[0101] Having described the invention in detail, it will be
apparent that modifications, variations, and equivalent embodiments
are possible without departing the scope of the invention defined
in the appended claims. It should be understood that all references
cited are incorporated herein by reference. Furthermore, it should
be appreciated that all examples in the present disclosure are
provided as non-limiting examples.
EXAMPLES
[0102] The following non-limiting examples are provided to further
illustrate the present invention. It should be appreciated by those
of skill in the art that the techniques disclosed in the examples
that follow represent approaches the inventors have found function
well in the practice of the invention, and thus can be considered
to constitute examples of modes for its practice. However, those of
skill in the art should, in light of the present disclosure,
appreciate that many changes can be made in the specific
embodiments that are disclosed and still obtain a like or similar
result without departing from the spirit and scope of the
invention.
Example 1
Non-Toxicity Studies
[0103] Nonclinical toxicity of VIT-45 is very low, as is normal for
Type I polynuclear iron (III)-hydroxide carbohydrate complexes. The
single dose toxicity is so low that the LD.sub.50 could not be
estimated and is higher than 2000 mg iron/kg b.w. Mice tested with
a single dose of 250 mg iron/kg b.w., injected within 2 seconds,
showed no signs of illness. The highest non-lethal dose level of
1000 mg iron/kg b.w. in mice and rats is also very high in
comparison to a single unit dose of, for example, 15 mg iron/kg
b.w. once per week in humans. These results provide factors of
about 70-fold a human dose, demonstrating a large safety margin for
acute toxicity of the product.
Example 2
Pharmokinetic Studies
[0104] Pharmacokinetic and red blood cell measurements of
.sup.52Fe/.sup.59Fe labelled VIT-45 following i.v. administration
using PET in 6 patients showed a red blood cell utilization from 61
to 99%. The 3 patients with iron deficiency anemia showed a
utilization of radiolabelled iron of 91 to 99% after 24 days,
compared to 61 to 84% for 3 patients with renal anaemia. The
terminal t.sub.1/2 for VIT-45 was calculated to be approximately 16
hours, compared to about 6 hours for iron sucrose. In two further
studies in patients with iron deficiency anemia, pharmacokinetic
analyses revealed increases in exposure roughly proportional with
VIT-45 dose (Cmax approximately 150 .mu.g/mL and 320 .mu.g/mL
following 500 mg and 1000 mg doses, respectively). VIT-45
demonstrated a monoexponential elimination pattern with a t.sub.1/2
in the range 7 to 18 hours. There was negligible renal
elimination.
Example 3
Efficacy Studies
[0105] The main pharmacodynamic effects of VIT-45 were transient
elevations of serum iron levels, TfS and serum ferritin. These
effects were seen in all studies (where measured), following both
single doses and repeated doses. The increase in serum ferritin
levels illustrated the replenishment of the depleted iron stores,
which is a well-identified and desired effect of iron therapy. In
addition, transiently elevated TfS indicated that iron binding
capacity was almost fully utilized following VIT-45 infusion.
[0106] Efficacy of iron replacement therapy is interpreted mainly
in terms of the ability to normalise Hb levels and iron stores. In
the multiple dose studies, patients demonstrated a
slowly-developing, sustained increase in Hb levels during study
participation. In one study, 37% and 48% of patients in Cohorts 1
and 2, respectively, had achieved normal Hb levels at the 4-week
follow-up visit, and 75% and 73%, respectively, had achieved a
.gtoreq.20 g/L increase in Hb on at least 1 occasion.
[0107] In another study (patients receiving regular haemodialysis),
the majority of patients (61.7%) achieved an increase of Hb of
.gtoreq.10 g/L at any point during the study. Serum ferritin and
TfS levels showed a more prolonged elevation following repeated
VIT-45 infusions, indicating a sustained replenishment of iron
stores. However, elevated levels of ferritin and TfS indicating
iron overload were avoided. In both of these studies, there was a
gradual decrease in transferrin over time, also indicating
successful iron replacement.
Example 4
Safety Assessments
[0108] Safety assessments were made in 73 patients with iron
deficiency anemia (27 single-dose, 46 repeated-dose), and 166
patients with renal anaemia (3 single-dose, 163 repeated-dose) who
received VIT-45 at individual iron doses of 100 mg up to 1000 mg
(cumulative doses of 100 to 2200 mg). These studies showed a safety
profile equal to, or exceeding, currently available parenteral iron
formulations.
[0109] In the single-dose studies, there were few adverse events
and no serious adverse events or withdrawals due to adverse events.
There were also no related clinically relevant adverse changes in
vital signs, 12-lead ECGs or laboratory safety tests.
[0110] In the repeated-dose studies, there were no deaths
attributed to VIT-45, while 10 patients experienced serious adverse
events. All of these cases occurred in patients with renal anaemia
receiving haemodialysis and were considered not related to the
VIT-45 treatment. Very few patients were withdrawn from the studies
due to treatment-emergent adverse events, and only 2 withdrawals
(due to allergic skin reactions) were considered possibly related
to treatment. In each of the repeated-dose studies, no patients
experienced clinically significant changes in 12-lead ECGs that
were related to treatment. There were no consistent changes in
laboratory safety parameters, although there was a low incidence
(total 6 patients) of laboratory values reported as
treatment-related treatment-emergent adverse events (elevated CRP,
AST, ALT and GGT, abnormal liver function tests and elevated
WBC).
[0111] Although many patients in these 2 studies had serum ferritin
above 500 .mu.g/L on at least 1 occasion during the study, very few
patients also had TfS values >50%. Generally, the elevations of
ferritin and TfS were of short duration. Iron overload was avoided
using the dosing schedules defined in the studies.
Example 5
Integrated Safety Studies
[0112] The following example demonstrates the safety and
effectiveness of parenteral VIT-45 in the treatment of anemia in a
variety of patient populations, as determined from several
integrated safety studies.
[0113] A total of 2429 subjects were treated with VIT-45 or control
agents over 10 studies that provide safety data for VIT-45. Of
these, 1709 subjects received VIT-45 (1095 in completed multicenter
studies, 584 in placebo-controlled, single-dose, crossover studies
and 30 in pharmacokinetic studies). The mean total dose of VIT-45
administered among the 1095 subjects in the completed multicenter
studies was approximately 1300 mg; however, some subjects received
VIT-45 doses as high as 3400 mg. The majority of the subjects
treated were able to receive their calculated iron requirement in
only 1 or 2 doses.
[0114] Table 2 provides a summary of VIT-45 studies described in
this example.
[0115] Study A was a single-center, single-dose escalation,
randomized, double-blind, placebo-controlled pharmacokinetic study.
Subjects were male and female, between 18 and 45 years of age,
inclusive, with mild iron-deficiency anemia. Treatment was a single
IV bolus injection of VIT-45 at 100 mg, 500 mg, 800 mg, or 1000 mg.
Examined pharmacokinetic parameters included total serum iron and
pharmacodynamic (serum ferritin and transferrin, iron binding
capacity, % TSATpost, hemoglobin, reticulocyte, and serum
transferrin receptor concentrations) endpoints. Examined safety
parameters included adverse events, clinical laboratory
evaluations, vital signs, ECG, and physical examinations.
[0116] Study B was a single-center, single-dose, open label,
uncontrolled pharmacokinetic study. Subjects were between 18 and 75
years of age with iron-deficiency or renal anemia with no other
cause of anaemia. Inclusion criteria included hemoglobin
concentration between 9 and 13 g/dL, no blood transfusions in the
previous 3 months, and no history of treatment with intravenous
iron in the last 2 weeks. Treatment was a single IV bolus injection
of VIT-45 at 100 mg labelled with .sup.52Fe and .sup.59Fe. Examined
primary pharmacokinetic parameters included the distribution of
.sup.52Fe and incorporation of .sup.59Fe into red blood cells.
Examined safety parameters included adverse events, clinical
laboratory evaluations, vital signs, and physical examinations.
[0117] Study C was an open-label, multicenter, randomized,
multiple-dose, active-controlled postpartum anemia study. Subjects
were female, postpartum within 10 days after delivery, with
hemoglobin .ltoreq.10 g/dL at Baseline based on the average of 2
hemoglobin values drawn .gtoreq.18 hours postpartum. Treatment was
once weekly doses of VIT-45 for six weeks. VIT-45 dosage was based
on the calculated iron deficit (.ltoreq.2500 mg total). Where
screening serum transferrin saturation (TSAT) was .ltoreq.20% or
screening ferritin was .ltoreq.50 ng/mL, dosage=pre-pregnancy
weight (kg).times.(15-baseline hemoglobin [g/dL]).times.2.4+500 mg.
Where screening TSAT was >20% and screening ferritin was >50
ng/mL, dosage=pre-pregnancy weight (kg).times.(15-baseline
hemoglobin [g/dL]).times.2.4. Infusion of VIT-45 was as follows:
.ltoreq.200 mg, administered as an undiluted intravenous push (IVP)
over 1-2 minutes; 300-400 mg, administered in 100 cc normal saline
solution (NSS) over 6 minutes; 500-1,000 mg administered in 250 cc
NSS over 15 minutes. For primary efficacy, "success" was defined as
an increase in hemoglobin of .gtoreq.2 g/dL anytime between
baseline and end of study or time of intervention, while "failure"
was defined as <2 g/dL increase in hemoglobin at all times
between baseline and end of study or time of intervention. Examined
safety parameters included adverse events, clinical laboratory
evaluations, vital signs, and physical examinations.
[0118] Study D was a multicenter, open-label, randomized,
active-controlled, multiple-dose postpartum anemia study. Subjects
were adult women .gtoreq.18 years old with postpartum anaemia
within 6 days after delivery. Treatment was administered
once-weekly for a maximum of 3 infusions. Patients received IV
infusions of 16.7 mL/min to deliver a maximum dose of 1000 mg iron
per infusion. Patients received VIT-45 infusions once weekly for up
to 3 occasions until the calculated cumulative dose was reached.
Patients .ltoreq.66 kg received a minimum dose of 200 mg and a
maximum dose of 15 mg iron/kg during each infusion. Patients >66
kg received a dose of 1000 mg on the first dosing occasion, and a
minimum dose of 200 mg and a maximum dose of 1000 mg at each
subsequent dosing. Doses of 200-400 mg were diluted in 100 cc NSS
and 500-1000 mg were diluted in 250 cc NSS. Primary efficacy was
examined as change from baseline levels of hemoglobin to Week 12.
Examined safety parameters included adverse events in the mother
and breast-fed infant, adverse events leading to discontinuation of
treatment, vital signs, 12-lead electrocardiogram (ECG), physical
examinations, and clinical laboratory panels.
[0119] Study E was a multicenter, open-label, randomized,
active-controlled, multiple-dose hemodialysis-associated anemia
study. Subjects were adult male or female subjects between the ages
of 18 and 80 years (inclusive) requiring haemodialysis with iron
deficiency secondary to chronic renal failure. Dosing started on
Day 1, Week 0 for both treatment arms and continued 2 or 3 times
weekly until the individual calculated cumulative dose was reached.
Patients received 200 mg VIT-45 during their scheduled
haemodialysis sessions (2-3 sessions/week) until the calculated
cumulative dose was reached. Cumulative total iron requirement was
calculated for each patient using the Ganzoni formula. Primary
Efficacy was examined as the percentage of patients reaching an
increase in hemoglobin .gtoreq.10 g/L at 4 weeks after baseline.
Examined safety parameters included adverse events, vital signs,
12-lead ECG, physical examinations, and clinical laboratory
evaluations.
[0120] Study F was a multicenter, open-label, multiple dose,
uncontrolled hemodialysis-associated anemia study. Subjects were
male and female patients 18-65 years of age, inclusive, with
haemodialysis-associated anaemia undergoing maintenance
haemodialysis. Treatment duration was a maximum of six weeks.
Patients received 200 mg VIT-45 during their scheduled
haemodialysis sessions (2-3 sessions/week) until the calculated
cumulative dose was reached. Cumulative total iron requirement was
calculated for each patient using the Ganzoni formula. Efficicacy
was examined as correction of iron deficiency and hemoglobin
concentration of the patient. Examined safety parameters included
adverse events, vital signs, 12-lead ECG, physical examinations,
haematology and blood chemistry profiles, and urea reduction
ratio.
[0121] Study G was a multicenter, multiple-dose open-label,
uncontrolled gastrointestinal disorder-associated anemia study.
Subjects were males and females between 18 and 60 years of age,
inclusive, with moderate stable iron-deficiency anemia secondary to
a gastrointestinal disorder and a calculated total iron requirement
.gtoreq.1000 mg; .gtoreq.50% of patients in each cohort were to
require .gtoreq.1500 mg total iron. Duration of treatment was
single doses at weekly intervals for up to 4 weeks (Cohort 1) or 2
weeks (Cohort 2). Administration of VIT-45 was by IV bolus
injection of 500 mg (Cohort 1) or 1000 mg (Cohort 2), where total
iron requirement for each patient, which determined how many weekly
infusions were received, was calculated using the formula of
Ganzoni. Examined pharmacokinetic parameters included total serum
iron and pharmacodynamic (hemoglobin, ferritin, TSAT) endpoints.
Examined safety parameters included adverse events, clinical
laboratory evaluations, vital signs, ECG, physical examinations,
and elevated serum ferritin (>500 .mu.g/L) AND elevated TSAT
(>45%).
[0122] Study H was a multicenter, multiple-dose randomized,
open-label, active-controlled gastrointestinal disorder-associated
anemia study. Subjects were males and females aged 18 to 80 years,
inclusive, with iron-deficiency anaemia secondary to chronic
inflammatory bowel disease (ulcerative colitis or Crohn's disease)
and a calculated total iron requirement of at least 1000 mg total
iron. Treatment was weekly VIT-45 infusions, with a maximum of 3
infusions permitted in a single treatment cycle. Administration
consisted of an infusion on Day 1, with subsequent infusions at
weekly intervals up to a maximum of 1000 mg iron per dose. The
doses were continued until the patient received the cumulative dose
based on their individual requirement for iron. Primary efficacy
was examined as change from baseline to Week 12 in hemoglobin.
Examined safety parameters included adverse events, vital signs,
12-lead ECG, physical examinations, and clinical laboratory
evaluations.
[0123] Study I was an open label, multiple-dose, multicenter,
randomized, active-control anemia due to heavy uterine bleeding
study. Subjects were females at least 18 years of age with
iron-deficiency anemia secondary to heavy uterine bleeding.
Duration of treatment was six weeks. VIT-45 dosage was based on the
calculated iron deficit as follows: where baseline TSAT .ltoreq.20%
or baseline ferritin .ltoreq.50 ng/mL, VIT-45 total dose in
mg=baseline weight (kg).times.(15-baseline hemoglobin
[g/dL]).times.2.4+500; where baseline TSAT >20% and baseline
ferritin >50 ng/mL, VIT-45 total dose in mg=baseline weight
(kg).times.(15-baseline hemoglobin [g/dL]).times.2.4. For
administration, .ltoreq.200 mg was administered as an undiluted IVP
over 1-2 minutes; 300-400 mg was administered in 100 cc NSS over 6
minutes; and 500-1,000 mg was administered in 250 cc NSS over 15
minutes. Primary efficacy was examined as the proportion of
subjects achieving success, defined as an increase in hemoglobin of
.gtoreq.2.0 g/dL anytime between baseline and end of study or time
of intervention. Examined safety parameters included adverse
events, clinical laboratory evaluations, vital signs, and physical
examinations.
[0124] Study J was a multicenter, single-dose blinded, randomized,
placebo-controlled crossover iron deficiency anemia study. Subjects
were male or female, at least 18 years of age, with a hemoglobin
.ltoreq.12 g/dL, TSAT .ltoreq.25%, and ferritin <300 ng/mL
(iron-deficiency anemia due to dialysis or non-dialysis dependent
chronic kidney disease or inflammatory bowel disease), or ferritin
.ltoreq.100 ng/mL (iron-deficiency anemia due to other conditions).
Treatment was two single doses seven days apart. Administration of
VIT-45 occurred over 15 minutes and was .ltoreq.1000 mg (15 mg/kg
for weight .ltoreq.66 kg). For pharmacokinetic variables, total
serum iron was assessed using Atomic Absorption methodology.
Examined safety parameters included adverse events, clinical
laboratory evaluations, vital signs, and physical examinations.
TABLE-US-00002 TABLE 2 Summary of Safety Studies of VIT-45 Study
Number Subjects Intravenous Dose(s) of VIT-45 Comparator
Pharmacokinetic Studies A Total: 32 Single doses of: Placebo
VIT-45: 24 100 mg via bolus injection 500 mg, 800 mg, 1000 mg
diluted in 250 mL of NSS administered by IV infusion over 15
minutes B Total: 6 Single dose of 100 mg labelled with .sup.52Fe
and .sup.59Fe None VIT-45: 6 administered as an IV injection over
10 minutes Studies in Subjects with Postpartum Anemia C Total: 352
Cumulative total iron requirement was calculated Oral iron (ferrous
VIT-45: 174 for each patient. Patients received IV infusions to
sulfate) 325 mg TID deliver a maximum dose of 1000 mg iron per for
6 weeks infusion. Patients received VIT-45 infusions once weekly
until the calculated cumulative dose was reached or a maximum of
2500 mg had been administered. Doses .ltoreq.200 mg were
administered IV push over 1-2 minutes; doses of 300-400 mg were
diluted in 100 cc NSS and administered over 6 minutes; doses of
500-1000 mg were diluted in 250 cc NSS and administered over 15
minutes. D Total: 344 Cumulative total iron requirement was
calculated Oral iron (ferrous VIT-45: 227 for each patient using
the Ganzoni formula. sulfate) 100 mg BID for 12 weeks Studies in
Subjects Undergoing Hemodialysis E Total: 237 Patients received 200
mg IV bolus injection of Venofer .RTM.; patients VIT-45: 119 study
drug during their scheduled hemodialysis received 200 mg IV
sessions (2-3 sessions/week) until the calculated injection over 10
cumulative dose was reached. Cumulative total minutes of study iron
requirement was calculated for each patient drug during their using
the Ganzoni formula. scheduled hemodialysis sessions (2-3
sessions/week) until the calculated cumulative dose was reached.
Cumulative total iron requirement was calculated for each patient
using the Ganzoni formula..sup.a F Total: 163 Patients received 200
mg IV push of study drug None VIT-45: 162 during their scheduled
hemodialysis sessions (2-3 sessions/week) until the calculated
cumulative dose was reached. Cumulative total iron requirement was
calculated for each patient using the Ganzoni formula. Studies in
Subjects with Gastrointestinal Disorders G Total: 46 500 mg or 1000
mg iron by IV infusion at weekly None VIT-45: 46 intervals for up
to 4 weeks (500 mg) or 2 weeks (1000 mg); maximum total dose of
2000 mg. The last dose could have been less, depending on the
calculated total iron requirement. Doses were diluted in 250 cc NSS
and administered by IV infusion over 15 minutes. H Total: 200
Cumulative total iron requirement was calculated Oral iron (ferrous
VIT-45: 137 for each patient using the Ganzoni formula. sulfate)
100 mg BID for 12 weeks Study in Subjects with Heavy Uterine
Bleeding I Total: 456 .ltoreq.1000 mg/week (15 mg/kg for weight
.ltoreq.66 kg); Oral iron (ferrous VIT-45: 230 patients received
VIT-45 infusions once weekly sulfate) 325 mg TID until the
calculated cumulative dose was reached or for 6 weeks a maximum of
2500 mg had been administered. Doses .ltoreq.200 mg were
administered IV push over 1-2 minutes; doses of 300-400 mg were
diluted in 100 cc NSS and administered over 6 minutes; doses of
500-1000 mg were diluted in 250 cc NSS and administered over 15
minutes. Study in Subjects with Iron Deficiency Anemia J Total: 594
Single dose of .ltoreq.1000 mg by IV infusion over 15 Placebo
VIT-45: 584 minutes (15 mg/kg for weight .ltoreq.66 kg). Doses
.ltoreq.500 mg were diluted in 100 cc NSS and doses of >500-1000
mg were diluted in 250 cc NSS. Pharmacokinetic subjects: single
1,000 mg dose by IV infusion
[0125] The majority of the subjects who received VIT-45 completed
the study. The incidence of premature discontinuations in the
completed multicenter studies was 10% in the VIT-45 group which is
comparable to that observed in the oral iron (9.6%) and Venofer
(13.6%) groups. Reasons for premature discontinuation were
generally comparable among the treatment groups, except that the
incidence of adverse events leading to discontinuation were higher
in the Venofer group (5.9%) compared to the VIT-45 (1.8%) and oral
iron (2.1%) groups, demonstrating the overall tolerability of
VIT-45.
[0126] The overall incidences of treatment-emergent adverse events
were comparable between the VIT-45 (49.5%) and oral iron (51.2%)
groups in the completed multicenter studies; the incidence in the
Venofer group was lower (39.0%); however, the number of subjects in
the VIT-45 group is almost 10-fold that of the Venofer group.
Treatment-emergent adverse events experienced by .gtoreq.2% of the
1095 VIT-45 subjects included headache (8.6%), abdominal pain
(2.5%), nausea (2.4%), blood phosphate decreased (2.4%),
hypertension (2.2%), nasopharyngitis (2.0%), and hypotension
(2.0%). As expected, the most notable difference between subjects
treated with VIT-45 and those treated with oral iron was for the
incidence of gastrointestinal events (31.0% vs. 12.8%),
specifically the incidences of constipation, diarrhea, nausea, and
vomiting, which were more than double that observed in the VIT-45
group.
[0127] In the calculated dose/first-dose 1,000 mg studies, no
statistically significant difference was observed between the
VIT-45 (49.5%) and oral iron (51.2%) groups for the overall
incidence of treatment-emergent adverse events. The incidence of
gastrointestinal disorders was statistically significantly
(p<0.0001) higher in the oral iron group (31.0%) compared to the
VIT-45 group (15.2%), while the incidences of adverse events
associated with investigations and skin and subcutaneous tissue
disorders were statistically significantly higher in the VIT-45
group (9.1% and 7.3%, respectively) compared to the oral iron group
(3.9% and 2.4%, respectively). Among the gastrointestinal
disorders, greater proportions of subjects in the oral iron group
than the VIT-45 group experienced constipation, nausea, diarrhea,
and vomiting, while a greater proportion of VIT-45 subjects
experienced abdominal pain than oral iron subjects. Among the
adverse events associated with investigations, greater proportions
of VIT-45 subjects experienced blood phosphate decreased and GGT
increased than oral iron subjects. Among the adverse events
associated with skin and subcutaneous tissue disorders, greater
proportions of VIT-45 subjects experienced rash and pruritus than
oral iron subjects.
[0128] The only drug-related treatment-emergent adverse events
reported by at least 2% of VIT-45 subjects in the calculated
dose/first-dose 1,000 mg studies were headache (3.9%) and blood
phosphate decreased (3.3%). The incidence of treatment-emergent
adverse events reported on the first day of dosing in the
calculated dose/first-dose 1,000 mg studies was statistically
significant higher in the VIT-45 group compared to the oral iron
group (6.8% vs. 2.7%). On the first day of dosing, the VIT-45 group
had statistically significantly greater proportions of subjects who
experienced general disorders and administration site conditions,
primarily events associated with the site of study drug infusion,
and skin and subcutaneous tissue disorders, primarily rash and
urticaria, compared to the oral iron group.
[0129] The overall incidence of treatment-emergent adverse events
was similar among VIT-45 subjects treated with either the 200 mg or
1000 mg doses. The only notable difference was for the higher
incidence of headache in the 1000-mg group, which was almost double
that observed for the 200-mg group. No meaningful trends were
apparent with respect to the incidence of treatment-emergent
adverse events when analyzed by gender, age, race, weight, or
etiology of anemia.
[0130] There were no deaths in the study attributed to VIT-45. The
incidence of other serious adverse events among VIT-45 subjects was
low (3% in all completed multicenter studies and 0.3% in the
placebo-controlled, single-dose crossover study) and none were
considered related to study drug. The incidence of premature
discontinuation due to adverse events was comparable between the
VIT-45 group (2.1%) and the other active treatment groups (3.1%
oral iron and 2.5% Venofer). The incidence of drug-related
treatment-emergent adverse events of hypersensitivity was 0.2%, the
same as that observed with oral iron (0.2%). Drug-related mild or
moderate hypotension was observed in 4 (0.2%) VIT-45 subjects, none
of which were considered serious, led to premature discontinuation,
or were symptomatic. Treatment-emergent adverse events indicative
of potential allergic reactions including rash, pruritus, and
urticaria were reported by <2% of subjects who were treated with
VIT-45; none of these events was considered serious and few led to
premature discontinuation.
[0131] Laboratory evaluations of mean changes from baseline and
potentially clinically significant values demonstrated no
clinically meaningful changes for the majority of the parameters
evaluated. However, during the conduct of the latter portion of the
clinical program, transient, asymptomatic decreases in blood
phosphate levels were observed among subjects treated with VIT-45.
The decreases were apparent approximately 7 days after the initial
dose of VIT-45 and the median time to recovery was approximately 2
weeks. No subjects reported an adverse event that was related to
serum phosphate and no subject discontinued from the study due to
decreased serum phosphate. The only predictor of change in serum
phosphate was that subjects with higher baseline serum phosphate
values had larger decreases in serum phosphate. The fact that the
majority of oral iron-treated subjects also had a post-baseline
decrease in phosphate and the negative correlation of baseline
serum phosphate with changes in serum phosphate for both the VIT-45
and oral iron treatment groups suggest that the mechanism is
intrinsic to iron therapy in this severely anemic population.
[0132] Overall, no clinically meaningful changes in vitals signs
evaluations were associated with VIT-45 administration.
[0133] Safety data from more than 1700 subjects demonstrate the
safety and tolerability of VIT-45.
* * * * *