Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics

Definitions

• This invention relates, in part, to methods of treating myelodysplastic syndromes, or ameliorating one or more symptoms thereof, which comprise the administration of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, as monotherapy or in combination with other therapeutic agents.
• the vitamin D compound can be administered in high doses to treat MDS, or ameliorate a symptom thereof, using intermittent administration to avoid side effects such as hypercalcemia.
• MDS Myelodysplastic syndrome
• MDS is primarily a disease of elderly people, with the median onset in the seventh decade of life. The median age of these subjects is 65 years, with ages ranging from the early second decade of life to as old as 80 years or older. However, myelodysplasia may also afflict children, who present with similar clinical manifestations as adults. See Heany et al, 1999, New Eng. J. Med. 340:1649-60. Genetic abnormalities such as Down's syndrome are present in approximately 30% of children with MDS and are thought to predispose such children to myelodysplastic syndrome. See id.
• MDS may be characterized as either primary or secondary, as subjects who survive malignancy treatment with certain chemotherapeutic agents or radiotherapy have a high incidence of developing secondary MDS or acute leukemia. See Zeidman et al, 1995, Haematologia (Budap) 27:23-8. About 60- 70% of subjects do not have an obvious exposure or cause for MDS and are classified as primary MDS subjects. However, a nonspecific history of exposure to indeterminable chemicals or radiation 10-15 years prior to onset of disease may be present in some subjects. Exposure to compounds including, but not limited to, benzene, insecticides, weed killers and fungicides is correlated with increased incidence of MDS.
• MDS is associated with severe cytopenias and their attendant clinical complications. Possible manifestations of these cytopenias include increased risk of infection due to neutropenia and neutrophil dysfunction, bleeding due to thrombocytopenia and platelet dysfunction, and fatigue due to anemia. Other complications are development of myelofibrosis, which can accelerate decline in blood counts and increase transfusion requirements. See Heany et al, 1999, New Eng. J. Med. 340:1649-60 and Lambertenghi- Deliliers et al, 1992, Leuk. Lymphoma 8:51-5. Another major clinical issue for patients with MDS is the potential for the disease to evolve to acute myeloid leukemia (AML). Any or all of these manifestations can lead to shortened survival of afflicted subjects.
• AML acute myeloid leukemia
• an initial hematopoietic stem cell injury can be caused by, among other factors, cytotoxic chemotherapy, radiation, virus, chemical exposure and genetic predisposition.
• the early stages of MDS are primarily characterized by cytopenias, including anemia, neutropenia, and thrombocytopenia.
• the disease course varies in each subject, with some cases behaving as an indolent disease and others behaving aggressively with a very short clinical course that quickly converts into an acute leukemia.
• FAB refractory anemia
• CMML chronic myelomonocytic leukemia
• the World Health Organization has proposed a classification system for MDS called the International Prognostic Scoring System (IPSS).
• IVS International Prognostic Scoring System
• This system classifies MDS disorders into four prognostic categories on the basis of percentage of bone marrow blasts, cytogenetic subgroup, and number of cytopenias. See Greenberg et al, 1998, Blood 89:2079-88 and Bennett, 2000, Int. J. Hematol 72:131-33. While the FAB classification system is still in use, the IPSS better predicts disease progression to acute myelogenous leukemia (AML) and patient survival.
• AML acute myelogenous leukemia
• MDS TREATMENTS The actual incidence of MDS in the U.S. is unknown. MDS was first considered a distinct disease in 1976 and occurrence was then estimated at 1500 new cases every year. At that time, only subjects with less than five percent myeloblasts were considered to have this disorder. Recent (1999) statistics estimate 13,000 new cases per year and about 1000 cases per year in children, surpassing chronic lymphocytic leukemia as the most common form of leukemia in the western hemisphere. The perception that the incidence is increasing may be due to improvements in recognition and criteria for diagnosis. The disease is found worldwide. EXISTING MDS TREATMENTS
• the current therapies of MDS are based on the mechanisms predominating at a particular phase in the disease process.
• bone marrow transplantation with a matched donor is the preferred treatment, but older subjects are often not candidates for such aggressive interventions since many are symptomatic from the anemia and are transfusion dependent.
• Hematopoietic growth factors or cytokines can be used to stimulate blood cell development and are effective in a subset of subjects.
• Other treatments include supportive care with transfusions of red cells and platelets combined with aggressive treatment of infections.
• many other classes of potentially therapeutic agents have also been assessed for efficacy in treating myelodysplastic syndrome, with limited success.
• Such classes include immunomodulators, cytotoxic agents, agents that affect RNA transcription, derivatives of vitamins A, E, and K, agents that specifically bind biological targets related to MDS, signal transduction inhibitors, cytoprotective agents, and arsenic- containing compounds.
• Bone marrow transplantation has been used in subjects with poor prognosis or late- stage MDS. See Epstein et al, 1985 Surg. Ann. 17:23-29. Unfortunately, bone marrow transplantation is invasive, painful for both the donor and recipient, and can cause severe to fatal complications in the recipient. Standard allogeneic transplant treatments rely on maximally tolerated doses of chemotherapy and total body irradiation to eradicate disease and immunosuppress the recipient to allow engraftment and prevent graft rejection. Post transplant immunosuppression is used to induce tolerance and control graft versus host disease. Thus, allogeneic transplantations have been essentially limited to treatment of young, healthy subjects and must be administered in specialized inpatient units.
• Transplant related mortality is approximately 20-25% under the best conditions, and can be as high as 30-35%. See Deeg et al, 2000, Le k. Res. 24:653-63. For this reason, very few transplants have been performed for subjects older than fifty years of age and have been limited to subjects with otherwise fatal diseases.
• Repeated transfusions in subjects with symptomatic refractory anemia are associated with clinical risks of the transmission of infectious diseases, transfusion reactions and cardiovascular overload.
• multiple transfusions such as about 20-30 transfusions, may cause secondary hemochromatosis, a condition that at least requires close monitoring of serum iron and often requires daily chelation therapy.
• Hematopoietic growth factors or cytokines are an alternative approach to treating MDS and stimulating blood cell development. See Dexter, 1987 Cell Sci. 88:1-6; Moore, 1991 Annu. Rev. Immunol. 9:159-91; and Besa, 1992, Med. Clin. North Am. 76(3): 599-617. Hematopoietic growth factors are hormones involved in the process of blood cell formation. The treatment involves stimulating the proliferation of a small number of self-renewing stem cells that give rise to lineage-specific progenitor cells that subsequently proliferate and differentiate to produce mature circulating blood cells. See Metcalf, 1985, Science 229:16; Dexter, 1987, J. Cell Sci.
• the most well- characterized growth factors include erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF).
• EPO erythropoietin
• GM-CSF granulocyte macrophage colony stimulating factor
• G-CSF granulocyte colony stimulating factor
• anemia of MDS is often serious and refractory to hematopoietic growth factors or cytokines.
• Anemia may aggravate conditions common to elderly subjects, including but not limited to congestive heart failure, coronary artery disease and chronic lung disease.
• a serum erythropoietin level of ⁇ 200 mU/mL is often predictive of a response to EPO, but responsiveness depends upon the stage of the disease with rates of 21% in refractory anemia and refractory anemia with ring sideroblasts, but only 8% in refractory anemia with excess blasts. See Hellstrom-Lindberg et al, 1997, Br. J. Haematol. 99:344-51 and Hellstrom- Lindberg, 1995, Br. J. Haematol. 89:67-71. Thus, treatment with EPO, G-CSF, or other growth factors is not effective to treat all, or even most, subjects with MDS.
• growth factors that have been administered in the treatment of MDS include thrombopoietin, interferon- ⁇ , interleukin-1, inter leukin-2, interleukin-3, interleukin-6, interleukin-8, interleukin-11, and interleukin-12. While many of these factors show promise in vitro and in preclinical studies, clinical trials to date have met with little to no success. See Schipperus et al, 1991 Br. J. Haematol. 77:515-22; Ganser et al, 2000, Ann. Hematol. 79:30-5; Musto et al, 2001, Haematologica 86:44-51; Gordon, Semin. Hematol.
• immunomodulators cytotoxic agents, agents that affect RNA transcription, derivatives of vitamins A, E, and K, agents that specifically bind biological targets related to MDS, signal transduction inhibitors, cytoprotective agents, and arsenic-containing compounds.
• immunomodulators that have been tested as possible therapeutic agents for MDS include anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), thalidomide, prednisone, cyclosporin A (CyA), dexamethasone, and pentoxifylline. See, e.g., Molldrem et al, 2002, Ann. Intern. Med.
• Tested cytotoxic agents include cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel, and cyclophosphamide.
• cytarabine melphalan
• topotecan fludarabine
• etoposide idarubicin
• daunorubicin daunorubicin
• mitoxantrone cisplatin
• paclitaxel paclitaxel
• cyclophosphamide cyclophosphamide.
• agents that affect RNA transcription include decitabine, 5-azacytidine, depsipeptides, and phenylbutyrate. See, e.g., Daskalakis et al, 2002, Blood 100:2957; Gryn et al, 2002, Leuk. Res. 26:893; Ballard et al, 2002, Curr. Med. Chem. 9:471; Imanishi et al, 2002, J. Clin. Endocrinol Metab. 87:4821; Silverman et al, 2002, J. Clin. Oncol. 20:2429; and Gore et al, 2002, Clin.
• Agents that specifically bind biological targets related to MDS that have been tested as potential therapies include anti-VEGF, gemtuzumab ozogamicin, and TNFR:Fc. See, e.g., Verstovsek et al, 2002, Br. J. Haematol. 118:151; List, 2002, Oncologist 1 Suppl 1:39; and Rosenfeld et al, 2002, Leuk. Res., 26:721.
• Signal transduction inhibitors that have been tried as therapeutic agents for MDS include farnesyl transferase inhibitors such as ZARNESTRATM and SARASARTM and tyrosine kinase inhibitors such as SU5416, SU6668, and PTK787/ZK222584.
• cytoprotective agent and arsenic-containing compound that have been assessed as potential therapies for MDS are amifostine and arsenic trioxide, respectively. See, e.g., Arboscello et al, 2002, AntiCancer Res. 22:1819; Invernizzi et al, 2002, Br. J.
• 5- Azacytidine is exceedingly toxic and can cause severe nausea and emesis in the subjects to whom it is administered. Also, the method of administration of this protocol is inconvenient for patients who must visit the administering clinic daily for the week of treatment. Finally, administration of 5-azacytidine initially causes the cytopenias of subjects with MDS to worsen before they later improve, which can be dangerous or lethal to some patients. Therefore, there remains a need for safe and effective methods of treating and managing MDS. Particularly, a method that is effective at treating the anemia associated with MDS and reducing the RBC transfusion requirements would be of clinical benefit.
• Vitamin D is a generic term for a family of secosteroids that have affinity for the vitamin D receptor, and are involved in the physiologic regulation of calcium and phosphate metabolism. See Harrison's Principles of Internal Medicine: Part Eleven, "Disorders of Bone and Mineral Metabolism,” E. Braunwald et al, (eds.), 1987, McGraw-Hill, New York at Chapter 335, pp. 1860- 1865, Stumpf et al, 1979, Science 206:1188-90, and Holick, 1995, Bone 17.107S- 1 IS. Vitamin D exhibits a complex set of actions and mechanisms of synthesis.
• Cholecalciferol (vitamin D 3 ) is synthesized in the skin following ultraviolet radiation from 7-dehydrocholesterol.
• Vitamin D 2 an analog of vitamin D 3
• Vitamin D 2 can be ingested from the diet.
• Two sequential hydroxylations of vitamin D 2 are necessary for full biological activity. The first hydroxylation, which takes place in the liver, results in the formation of 25- hydroxycholecalciferol, while the second hydroxylation takes place in the kidney and results in the formation of the most potent biological metabolite of vitamin D: l ⁇ ,25- dihydroxycholecalciferol (also known as calcitriol).
• Calcitriol maintains calcium homeostasis by modulating intestinal abso ⁇ tion, urinary excretion, and mobilization from skeletal bone. These effects can be exerted through both genomic and non-genomic pathways.
• the genomic responses are mediated by calcitriol binding the nuclear vitamin D receptor (VDR).
• VDR is a ligand-activated transcription factor that activates transcription of genes regulated by the vitamin D response element within their promoter/enhancer regions. See Mangelsdorf et al, 1995, Cell 83:835-9.
• the non- genomic pathways are mediated by an as-yet uncharacterized membrane- bound receptor.
• VDR has been found in cells from diverse organs not involved in calcium homeostasis. See Miller et al, 1992, Cancer Res. 52:515- 520.
• vitamin D compounds have been implicated in osteogenesis, modulation of the immune response, modulation of insulin secretion by pancreatic B cells, muscle cell function, and differentiation and growth of epidermal and hematopoietic tissues.
• vitamin D compounds and analogs possess potent anti-leukemic activity by virtue of their ability to induce differentiation of leukemic cells to non-malignant macrophages (monocytes) and are therefore useful in the treatment of leukemia.
• monocytes non-malignant macrophages
• Antiproliferative and differentiating actions of calcitriol and other vitamin D 3 analogs have also been reported with respect to the treatment of prostate cancer. See Bishop et al, U.S. Patent No. 5,795,882.
• Vitamin D compounds have also been implicated in the treatment of skin cancer (See Chida et al, 1985, Cancer Res. 45:5426-5430), colon cancer (See Disman et al, 1987, Cancer Res. 47:21-25), and lung cancer (See Sato et al, 1982, J. Exp. Med. 138:445-446). Other reports suggesting important therapeutic uses of vitamin D compounds are summarized in Rodriguez et al, U.S. Patent No. 6,034,079.
• Vitamin D compounds have also been administered in combination with other pharmaceutical agents, in particular cytotoxic agents, for the treatment of hyperproliferative disease.
• cytotoxic agents for the treatment of hyperproliferative disease.
• pretreatment of hyperproliferative cells with Vitamin D compounds followed by treatment with cytotoxic agents enhances the efficacy of the cytotoxic agents (U.S. Patent Nos. 6,087,350 and 6,559,139).
• vitamin D compounds may result in substantial therapeutic benefits, their use as a treatment for cancer or MDS has been severely limited by the effects that these compounds have on calcium metabolism.
• vitamin D compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of calcitriol and other vitamin D compounds to treat cancer or MDS has been precluded, or severely limited, by the risk of hypercalcemia.
• HDPA high dose pulse administration
• the active vitamin D compound may be administered no more than every three days, for example, once a week at a dose of at least 0.12 ⁇ g/kg per day (8.4 ⁇ g in a 70 kg person).
• Pharmaceutical compositions used in the HDPA regimen of 6,521,608 comprise 5-100 ⁇ g of active vitamin D compound and may be administered in the form for oral, intravenous, intramuscular, topical, transdermal, sublingual, intranasal, intratumoral, or other preparations.
• HDPA of calcitriol was shown to produce no dose-limiting toxicity and to produce mean peak calcitriol levels within the therapeutic range. Beer et al, Cancer 91 :2431-39 (2001).
• This invention encompasses methods and compositions for the treatment of myelodysplastic syndrome (MDS), or ameliorating a symptom thereof, particularly the anemia of MDS, comprising administering to a subject in need thereof a therapeutically effective dose of vitamin D compounds, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof, while avoiding or minimizing hypercalcemia.
• MDS myelodysplastic syndrome
• These methods and compositions can be used for the treatment of MDS, or amelioration of a symptom thereof, with few or no associated symptoms of hypercalcemia.
• the methods of the invention comprise administering intermittently a therapeutically effective dose of a vitamin D compound and optionally administering one or more additional active agents.
• the dose of the vitamin D compound can be a high dose, as intermittent administration of the vitamin D compounds according to the methods of the invention allows a high dose to be administered to a subject without causing hypercalcemia.
• the vitamin D compound can be any vitamin D compound without limitation.
• the vitamin D compound is an active vitamin D compound such as calcitriol.
• a therapeutically effective dose of a vitamin D compound can be a dose between about 3 ⁇ g/day to about 300 ⁇ g/day, or any range of doses therein as described below.
• the vitamin D compounds can be administered not more than once every three days.
• the vitamin D compound is administered about once per week.
• a therapeutically effective dose of an active vitamin D compound is preferably between about 3 ⁇ g/day to about 300 ⁇ g/day, more preferably between about 5 ⁇ g/day to about 200 ⁇ g/day, more preferably between about 15 ⁇ g/day to about 105 ⁇ g/day, more preferably between about 15 ⁇ g/day to about 90 ⁇ g/day, more preferably between about 20 ⁇ g/day to about 80 ⁇ g/day, more preferably between about 35 ⁇ g/day to about 75 ⁇ g/day, more preferably between about 30 ⁇ g/day to about 60 ⁇ g/day, and even more preferably about 45 ⁇ g.
• the therapeutically effective dose of a vitamin D compound safely achieves peak plasma concentrations ofthe vitamin D compound of at least about 0.5 nM, more preferably about 1 - 7 nM, and even more preferably about 3 - 5 nM. While any vitamin D compound may be used according to the methods of the invention, preferred vitamin D compounds achieve peak plasma concentrations rapidly and are eliminated quickly.
• the invention provides methods for the treatment of MDS, or amelioration of a symptom thereof, comprising administering a therapeutically effective dose of a vitamin D compound in combination with one or more additional active agents.
• the therapeutically effective dose of the vitamin D compound can be any dose, in combination with the one or more additional active agents, effective to treat MDS or ameliorate a symptom thereof.
• the therapeutically effective dose of the vitamin D compound is a high dose.
• the additional active agents can be one or more growth factors, e.g., hematopoietic growth factors or cytokines; immunomodulators; cytotoxic agents, e.g., antimetabolites, anti-microtubule agents, alkylating agents, platinum agents, anthracyclines, antibiotic agents, or topoisomerase inhibitors; agents that affect RNA transcription; derivatives of vitamins A, E, and K; agents that specifically bind biological targets related to MDS; signal transduction inhibitors; cytoprotective agents; or arsenic-containing compounds.
• growth factors e.g., hematopoietic growth factors or cytokines
• immunomodulators e.g., cytotoxic agents, e.g., antimetabolites, anti-microtubule agents, alkylating agents, platinum agents, anthracyclines, antibiotic agents, or topoisomerase inhibitors
• agents that affect RNA transcription derivatives of vitamins A, E, and K
• hematopoietic growth factors or cytokines examples include, but are not limited to, erythropoietin (EPO) and granulocyte colony stimulating factor (G-CSF), and more particularly recombinant human erythropoietin (r-HuEPO), and recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF).
• EPO erythropoietin
• G-CSF granulocyte colony stimulating factor
• r-HuEPO recombinant human erythropoietin
• r-metHuG-CSF methionyl human granulocyte colony stimulating factor
• the present invention provides pharmaceutical compositions comprising one or more vitamin D compounds and one or more additional active agents.
• a vitamin D compound and optionally one or more additional active agents can be administered in the form of a pharmaceutical composition, a single unit dosage form, or article of manufacture suitable for use in treating MDS, or ameliorating a symptom thereof, which comprises one or more vitamin D compounds, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof.
• the vitamin D compound(s) and optionally one or more additional active agents can be formulated in any pharmaceutical composition known to those of skill in the art.
• the vitamin D compounds are administered in oral or intravenous formulations.
• Preferred oral formulations include emulsion pre-concentrates which comprise one or more vitamin D compounds, a lipophilic phase component, and a surfactant.
• the compositions for the treatment of MDS, or amelioration of a symptom thereof comprise a therapeutically effective dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in combination with one or more additional active agents.
• the methods and compositions of the present invention are useful for the treatment of MDS, or amelioration of a symptom thereof, in a subject, preferably a human subject.
• the methods and compositions of the present invention can be used for the treatment of MDS, or amelioration of a symptom thereof, with active vitamin D compounds such as calcitriol, while minimizing or avoiding the effects of hypercalcemia.
• Fig. 1 provides plasma concentrations of calcitriol as a function of time.
• Figs. 2A-2C provide hemoglobin concentration (in grams per deciliter) and red blood cell transfusion frequency (in units transfused) as a function of time for patient #1 (Fig. 2A), patient #2 (Fig. 2B), and patient # 3 (Fig. 2C).
• the present invention provides methods and compositions for treating myelodysplastic syndrome, or ameliorating a symptom thereof, with one or more vitamin D compounds, preferably an active vitamin D compound such as calcitriol, while minimizing or eliminating the risks of hypercalcemia.
• one or more vitamin D compounds are administered in combination with one or more additional active agents.
• Active vitamin D compound refers to a vitamin D compound that is biologically active when administered to a subject or contacted with cells.
• the biological activity of a vitamin D compound can be assessed by assays described herein or well-known to one of skill in the art such as, e.g., immunoassays (e.g., enzyme-linked immunoassays ("ELIS As")) that measure the expression of a gene.
• Vitamin D compounds exist in several forms with several different levels of activity in the body.
• a vitamin D compound may be partially activated by first undergoing hydroxylation in the liver to 25- hydroxycholecalciferol and then may be fully activated in the kidney to l ⁇ ,25- dihydroxycholecalciferol, which is also known as, inter alia, "calcitriol.” Calcitriol, however, is the principal biologically active form of vitamin D in humans and does not require further modification in the body for immediate utilization.
• Calcemic index refers to a measure of the relative ability of a drug to generate a calcemic response. Examples of such measurement are demonstrated in Bouillon et al, 1995, Endocrine Reviews 16:200-7. A calcemic index of 1 corresponds to the relative calcemic activity of calcitriol. A calcemic index of about 0.01 corresponds to the calcemic activity of calcipotriol. A calcemic index of 0.5 would correspond to a drug having approximately half the calcemic activity of calcitriol.
• the calcemic index of a drug can vary depending on the assay used, e.g., whether measuring stimulation of intestinal calcium absorption (ICA) or bone calcium mobilizing activity (BCM), as reported in Hurwitz et al, 1967, J. Ni.tr. 91 :319- 323 and Yamada et al, 1988, Mol Cell. Endocrinol 59:57-66.
• Relative calcemic activity is best expressed in relation to the calcemic activity of calcitriol, which is one ofthe best characterized vitamin D compounds.
• “Clinical hypercalcemia” refers to one or more of the signs or symptoms of hypercalcemia.
• Hypercalcemia can be life- threatening and is thus typically to be avoided in vitamin D compound administration
• Embodision pre-concentrate refers to a formulation capable of providing an emulsion upon contact with a polar medium such as water.
• emulsion refers to a colloidal dispersion comprising a polar medium such as water and organic components including but not limited to hydrophobic, i.e. lipophilic, organic components and encompasses both conventional emulsions and sub-micron droplet emulsions.
• sub-micron droplet emulsion refers to an emulsion wherein the droplets or particles forming the colloidal dispersion of organic components have an average maximum dimension of less than about 1000 nm.
• Hypercalcemia refers to a condition in which the blood calcium concentration is greater than normal (although the normal value can vary slightly depending on the measuring technique used). Although the concentration that is considered “normal” will vary slightly with variation in measurement techniques, a value above 10.5 mg/dL in humans is considered hypercalcemia. Hypercalcemia can be divided into grades 0-4.
• Grade 0 corresponds to a value of blood calcium concentration that is less than 10.6 mg/dL
• Grade 1 corresponds to a value of blood calcium concentration of 10.6-11.5 mg/dL
• Grade 2 corresponds to a value of blood calcium concentration of 11.6-12.5 mg/dL
• Grade 3 corresponds to a value of blood calcium concentration of 12.6-13.5 mg/dL
• Grade 4 corresponds to a value of blood calcium concentration that is greater than 13.5 mg/dL. See, e.g., U.S. Patent No. 6,521,608 .
• In combination refers to the use of more than one therapeutic agent.
• the use of the term “in combination” does not restrict the order in which therapeutic agents are administered to a subject with MDS.
• a first therapeutic agent can be administered prior to, concurrently with, after, or within any cycling regimen involving the administration of a second therapeutic agent to a subject with MDS.
• the first therapeutic agent can be administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before a second therapeutic agent; or the first therapeutic agent can be administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after a second therapeutic agent.
• isopropanol an example of a “constitutional isomer” of propanol, wherein the compounds have the same molecular formula but differ in the placement of the connections between the atoms.
• An example of a “stereoisomer” is an "enantiomer,” which is any compound that is the mirror image of another compound.
• Another example of a stereoisomer is a diastereomer, which is any stereoisomer that contains more than one chiral center but is not an enantiomer.
• Intermittent administration refers to a method of achieving periodically high blood concentrations of vitamin D compounds without the onset of hypercalcemia.
• the method of intermittent administration comprises periodically dosing a subject with a high level of one or more vitamin D compounds.
• Intermittent administration may comprise, for example, but not by way of limitation, administering the one or more vitamin D compounds not more than every three days, about once every four days, about once every five days, about once every six days, about once per week, about once every nine days, about once every two weeks, about once every three weeks, or about once every four weeks.
• the period of intermittent administration may continue for one, two, three, or four weeks, or one, two, three, four, five, or six months, or longer.
• the intermittent dosing schedules can comprise administration of vitamin D compounds that is more or less frequent than those mentioned thus far, or that continues for longer or shorter treatment periods, depending on the pharmacokinetics and pharmacodynamics of the pharmaceutical agent employed.
• One of skill in the art will readily understand the potential need to adjust the periodic dosing regimens, and that any periodic dosing schedule that includes the administration of high doses of vitamin D compounds without the onset of hypercalcemia is within the scope of the invention.
• An example of a dosing schedule that can be used by the methods ofthe present invention is provided in U.S. Patent No. 6,521,608 , which is incorporated by reference.
• Methodabolite refers to a substance that results after the body has processed, i.e. metabolized, another substance.
• An example of a series of metabolites may begin with 1,25-dihydroxyergocalciferol, the most active form of vitamin D 2 , which is a metabolite of 25-hydroxyergocalciferol, which is a metabolite of ergocalciferol (vitamin D 2 ), which is a metabolite of ergosterol.
• Another example of a series of metabolites may begin with 1,25-dihydroxycholecalciferol (calcitriol), which is a metabolite of 25-hydroxycholecalciferol, which is a metabolite of cholecalciferol (vitamin D3), which is a metabolite of 7- dehydrocholesterol.
• calcitriol 1,25-dihydroxycholecalciferol
• vitamin D3 cholecalciferol
• tachysterol which is a metabolite of dihydrotachysterol, which is a metabolite of 25-hydroxydihydrotachysterol.
• Non-hypercalcemic vitamin D compound refers to a vitamin D compound that has less of a tendency to produce the onset of hypercalcemia than a comparable dosage of calcitriol as assessed by assays well-known to one of skill in the art.
• non- hypercalcemic vitamin D compounds include analogs of calcitriol such as Ro23-7553 and Ro24-5531 (l ⁇ ,25-dihydroxy-16-ene- 23-yne-26,27-hexafluorocholecalciferol) available from Hoffmann-LaRoche.
• Other examples of non-hypercalcemic vitamin D compounds can be found in U.S. Patent No. 4,717,721, which is incorporated by reference herein in its entirety.
• “Pharmaceutical formulation” refers to a composition comprising ingredients that are pharmaceutically acceptable for their intended use.
• “Pharmaceutical agent” refers to one or more vitamin D compounds or one or more vitamin D compounds in combination with one or more active ingredients that are not vitamin D compounds, including but not limited to, bisphosphonates.
• the pharmaceutical agent can be administered in combination with other active ingredients as well, such as, for example, the administration of vitamin D compounds in combination with hematopoietic growth factors or cytokines in the treatment of MDS.
• Precursor refers to a compound that can be transformed into another compound that is biologically active.
• An example of a series of precursors may begin with ergosterol, which is the precursor to ergocalciferol (vitamin D 2 ), which is the precursor to 25-hydroxyergocalciferol, which is the precursor to 1,25- dihydroxyergocalciferol, the most active form of vitamin D 2 .
• Another example of a series of precursors may begin with 7- dehydrocholesterol, which is the precursor to cholecalciferol (vitamin D3), which is the precursor to 25- hydroxycholecalciferol, which is the precursor to 1,25- dihydroxycholecalciferol (calcitriol).
• tachysterol which is the precursor to dihydrotachysterol, which is the precursor to 25 -hydroxydihydrotachysterol .
• Refractory and “non-responsive” refer to subjects treated with a currently available therapeutic agent for MDS which is not clinically adequate to relieve one or more symptoms associated with the MDS. Typically, such subjects suffer from severe, persistently active disease and require additional therapy to ameliorate the symptoms associated with their MDS.
• Synergistic refers to a combination of therapeutic agents which is more effective than the additive effects of any two or more single agents.
• a synergistic effect of a combination of therapeutic agents permits the use of lower dosages of one or more of the agents and/or less frequent administration of said agents to a subject with MDS.
• the ability to utilize lower dosages of therapeutic agents and/or to administer said agents less frequently reduces the toxicity associated with the administration of said agents without reducing the efficacy of said agents in the treatment of MDS, or amelioration of a symptom thereof.
• a synergistic effect can result in improved efficacy of agents in the treatment of MDS, or amelioration of a symptom thereof.
• the synergistic effect of a combination of therapeutic agents may avoid or reduce adverse or unwanted side effects associated with the use of any single therapy.
• Subject and “patient” are used interchangeably.
• the terms “subject” and “subjects” refer to an animal, preferably a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey, such as a cynomolgus monkey, and a human), and more preferably a human.
• a non-primate e.g., a cow, pig, horse, cat, dog, rat, and mouse
• a primate e.g., a monkey, such as a cynomolgus monkey, and a human
• “Therapeutic agents” refer to any agent(s) which can be used in the prevention or treatment of MDS, or amelioration of a symptom thereof.
• the term “therapeutic agents” refers to one or more vitamin D compounds.
• the term “therapeutic agents” does not refer a vitamin D compound.
• a therapeutic agent is known to be useful, or has been or is currently being used, to prevent or impede the development, onset or progression of MDS, or ameliorate the symptoms of MDS.
• a “therapeutically effective dose” refers to a dose of an ingredient that can achieve the desired therapeutic or prophylactic effects, such as, for example, a dose that can achieve a blood level of a vitamin D compound that is above normal for a sufficient period of time to have therapeutic benefit without clinically relevant toxicity.
• a therapeutically effective dose of vitamin D compounds can range from about 3 ⁇ g to about 300 ⁇ g, or any range of amounts therein. Higher peak blood levels of vitamin D compounds are associated with increased efficacy but at some point the benefit may be limited by toxicity. Specific regimens of administration allow higher doses to be administered safely, that is, without the onset of symptoms associated with hypercalcemia.
• a therapeutically effective amount of a vitamin D compound is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 ⁇ g or more.
• a therapeutically effective dose of an active vitamin D compound is preferably between about 3 ⁇ g/day to about 300 ⁇ g/day, more preferably between about 5 ⁇ g/day to about 200 ⁇ g/day, more preferably between about 15 ⁇ g/day to about 105 ⁇ g/day, more preferably between about 15 ⁇ g/day to about 90 ⁇ g/day, more preferably between about 20 ⁇ g/day to about 80 ⁇ g/day, more preferably between about 35 ⁇ g/day to about 75 ⁇ g/day, more preferably between about 30 ⁇ g/day to about 60 ⁇ g/day, and even more preferably about 45 ⁇ g.
• the therapeutically effective dose of vitamin D compound safely achieves peak plasma concentrations of the vitamin D compound of at least about 0.5 nM, more preferably about 1 - 7 nM, and even more preferably about 3 - 5 nM.
• Treatment refers to administration of one or more prophylactic or therapeutic agents either before or after the onset of symptoms of MDS.
• “Treat,” “treatment” and “treating” further include “managing” MDS, which includes lengthening the time a subject remains in remission and/or preventing the reoccurrence of MDS in subjects at risk of suffering MDS.
• “Treat,” “treatment” and “treating” further include preventing the recurrence or onset of one or more symptoms of MDS in a subject.
• the symptoms associated with MDS include but are not limited to anemia, thrombocytopenia, neutropenia, bicytopenia (two deficient cell lines), and pancytopenia (three deficient cell lines).
• vitamin D compound refers to any form of chemical compound with an affinity for the vitamin D receptor (VDR).
• VDR vitamin D receptor
• the vitamin D compounds of the present invention can concentrate in the blood to a therapeutically effective level.
• the VDR is a ligand-activated transcription factor, or intracellular receptor, which initiates transcription by binding to the vitamin D response element within the promoter/enhancer region of target genes.
• vitamin D compounds within the scope of the invention include but are not limited to calcitriol, 1,25- dihydroxyergocalciferol, calcifediol, 25-hydroxyergocalciferol, ergocalciferol, cholecalciferol, doxercalciferol, dihydrotachysterol, paracalcitol, as well as the derivatives, analogs, homologs, precursors and metabolites thereof.
• Preferred vitamin D compounds are active vitamin D compounds and include but are not limited to calcitriol and all of its derivatives, analogs, homologs, precursors and metabolites. The most preferred vitamin D compound is calcitriol.
• the vitamin D compound can be any compound that binds to a vitamin D receptor and thus can be any vitamin D compound known to one of skill in the art.
• vitamin D traditionally refers to ergocalciferol (vitamin D 2 ) and cholecalciferol (vitamin D3), but the present invention encompasses the use of any vitamin D compound or its derivatives, analogs, homologs, precursors and metabolites.
• vitamin D compound not only includes, for example, naturally occurring ergocalciferol and cholecalciferol, but also includes their respective precursors ergosterol and 7-dehydrocholesterol.
• vitamin D compound also includes the activated forms or metabolites of ergocalciferol and cholecalciferol, which include 25-hydroxyergocalciferol and 25- hydroxycholecalciferol (calcifediol) in addition to the most active forms, which are 1,25-dihydroxyergocalciferol and 1,25-dihydroxycholecalciferol (calcitriol).
• activated forms or metabolites of ergocalciferol and cholecalciferol which include 25-hydroxyergocalciferol and 25- hydroxycholecalciferol (calcifediol) in addition to the most active forms, which are 1,25-dihydroxyergocalciferol and 1,25-dihydroxycholecalciferol (calcitriol).
• the chemical structure of calcitriol is as follows:
• the vitamin D compound can be isolated from natural sources or synthesized by methods known to those of skill in the art.
• An example of a synthetic vitamin D analog is dihydrotachysterol.
• Dihydrotachysterol is a synthetic reduction product of tachysterol.
• Tachysterol is a byproduct formed during the irradiation of 7-dehydrocholesterol, the precursor to vitamin D 3 .
• Dihydrotachysterol is ten times more active than its precursor tachysterol and is activated in the liver to the even more active 25-hydroxydihydrotachysterol.
• Other examples of synthetic vitamin D analogs are paricalcitol and doxercalciferol, which can be used to lower parathyroid hormone levels.
• Another example of a synthetic vitamin D analog is alfacalcidol, which is currently in clinical use in Canada for the treatment and prevention of renal bone disease, rickets, hypoparathyroidism and osteoporosis.
• vitamin D compounds used in the present invention comprise active vitamin D compounds. While not intending to be bound by any particular theory or mechanism of action, vitamin D compounds can become activated, for example, through (1) ultraviolet conversion of 7-dehydrocholesterol in the skin to vitamin D 3 (cholecalciferol) and (2) dietary intake of either vitamin D 2 (ergocalciferol) or vitamin D 3 . Both vitamin D 2 and vitamin D 3 compounds, for example, become fully active on target tissues when metabolically activated in the liver and kidney.
• the next step in activation can be the introduction of a hydroxyl group in the side chain at the C-25 position by a hepatic enzyme known as CYP 27 (a vitamin D-25-hydroxylase).
• CYP 27 a vitamin D-25-hydroxylase
• the partially activated vitamin D 2 and D 3 compounds are known as, ter alia, 25-hydroxyergocalciferol and 25-hydroxycholecalciferol, respectively.
• the active vitamin D compounds ofthe present invention include but are not limited to the analogs, homologs and derivatives of vitamin D compounds described in the following patents, each of which is incorporated by reference herein in its entirety: U.S. Patent Nos.
• 4,391,802 (l ⁇ -hydroxy vitamin D derivatives); 4,717,721 (l ⁇ -hydroxy derivatives with a 17- side chain greater in length than the cholesterol or ergosterol side chains); 4,851,401 (cyclopentano- vitamin D analogs); 5,145,846 (vitamin D 3 analogs with alkynyl, alkenyl and alkanyl side chains); 5,120,722 (trihydroxycalciferol); 5,547,947 (fluorocholecalciferol compounds); 5,446,035 (methyl substituted vitamin D); 5,411,949 (23-oxa-derivatives); 5,237,110 (19-nor- vitamin D compounds); 4,857,518 (hydroxylated 24-homo-vitamin D derivatives).
• active vitamin D compounds in clinical use include but are not limited to investigational drugs from Leo Pharmaceutical such as EB 1089 (24a,26a,27a-trihomo-22,24-diene-l ⁇ a,25-(OH) 2 - D 3 ), KH 1060 (20-epi-22-oxa- 24a,26a,27a-trihomo-l ⁇ ,25-(OH) 2 -D 3 ), MC 1288 and MC 903 (calcitriol); Roche Pharmaceutical drugs such as l,25-(OH)2-16-ene-D3, l,25-(OH) 2 -16-ene- 23- yne-D 3 and 25-(OH) 2 -16-ene-23-yne-D 3 ; Chugai Pharmaceuticals such as 22- oxacalcitriol (22-oxa-l ⁇
• Vitamin D analogs also include topical preparations of vitamin D compounds, such as calcipotriene (DovONEX®) and Tacalcitol (CURATODERM®).
• calcipotriene DovONEX®
• CURATODERM® Tacalcitol
• active vitamin D compound formulations ROCALTROL®, which is available from Roche
• CALCUEX® which is available from Abbott.
• active vitamin D compounds and their derivatives, analogs, homologs, precursors and metabolites include but are not limited to l ⁇ ,25-(OH) 2 -26,27-d 6 -D 3 ; l ⁇ ,25-(OH) 2 -22-ene-D 3 ; l ⁇ -(OH) 2 -D 3 ; l ⁇ ,25-(OH) 2 - D 2 ; l ⁇ ,25-(OH) 2 -D 4 ; l ⁇ ,24,25-(OH) 3 -D 3 ; l ⁇ ,24,25-(OH) 3 -D 2 ; l ⁇ ,24,25-(OH) 3 -D 4 ; l ⁇ -(OH)-25-FD 3 ; l ⁇ -(OH)-25-FD 4 ; l ⁇ (OH)-25-FD 2 ; l ,24-(OH) 2 -D 4 ; l ⁇ ,24- (OH) 2 -D 3 ; l ⁇ ,24- (OH) 2 -
• preferred vitamin D compounds have pharmacokinetic properties that make them more suitable for the below-described methods than other vitamin D compounds.
• preferred vitamin D compounds achieve peak plasma concentrations rapidly, e.g., within about four hours, and are eliminated quickly, e.g., with an elimination half-life of about 12 hours or fewer.
• the elimination half-life describes the time for the plasma concentration of the agent to be reduced by 50%, while eliminated in this context is meant to refer to the plasma concentrations below about 0.5 nM.
• endogenous vitamin D plasma concentrations vary from subject to subject, they are typically about 0.16 nM.
• Calcitriol is an example of such a preferred vitamin D compound with desirable pharmacokinetic properties as described above. While not intending to be bound to any particular theory or mechanism of action, it is believed that vitamin D compounds with these pharmacokinetic properties can initiate the therapeutic biological response during the brief period of elevated concentration, then quickly fall below the threshold concentration that facilitates calcium release, thereby minimizing hypercalcemia.
• the active vitamin D compound is calcitriol.
• the vitamin D compounds used in the present invention also comprise non- hypercalcemic vitamin D compounds.
• the vitamin D compound is not a non-hypercalcemic vitamin D compound.
• Non-hypercalcemic vitamin D compounds have less of a tendency to produce the onset of hypercalcemia than a comparable dosage of calcitriol as assessed by assays well-known to one of skill in the art.
• non-hypercalcemic vitamin D compounds include analogs of calcitriol such as Ro23-7553 and Ro24-5531 (l ⁇ ,25-dihydroxy-16-ene- 23-yne-26,27-hexafluorocholecalciferol) available from Hoffmann-LaRoche.
• Other examples of non- hypercalcemic vitamin D compounds can be found in U.S. Patent No. 4,717,721, which is incorporated by reference herein in its entirety.
• the foregoing description of vitamin D compounds is not exhaustive and is merely exemplary of all compounds capable of binding to VDRs.
• this invention encompasses all vitamin D compounds, i.e. all compounds capable of binding to VDRs, and the derivatives, analogs, homologs, precursors, metabolites, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs thereof.
• the present invention provides compositions for treatment of MDS, or amelioration of one or more symptoms thereof, by administration of a vitamin D compound in combination with one or more additional active agent(s).
• the additional active agent can be any active agent having a therapeutic effect to treat MDS, or ameliorate a symptom thereof, that is known to one of skill in the art without limitation.
• Active agents include, but are not limited to, small molecules, synthetic drugs, peptides, polypeptides, proteins, nucleic acids (e.g., DNA and RNA nucleotides including, but not limited to, antisense nucleotide sequences, triple helices and nucleotide sequences encoding biologically active proteins, polypeptides or peptides), antibodies, synthetic or natural inorganic molecules, mimetic agents, and synthetic or natural organic molecules. Any agent which is known to be useful, or which has been used or is currently being used for the treatment of MDS, or amelioration of one or more symptoms associated with MDS, can be used in combination with a vitamin D compound in accordance with the invention described herein.
• nucleic acids e.g., DNA and RNA nucleotides including, but not limited to, antisense nucleotide sequences, triple helices and nucleotide sequences encoding biologically active proteins, polypeptides or peptides
• antibodies synthetic or natural inorganic
• compositions of the invention encompass administration of a vitamin D compound of the invention in conjunction with one or more additional active agents that have combinatorial, synergistic, additive, or other therapeutic effects.
• a vitamin D compound of the invention can be administered with a growth factor such as a cytokine or hematopoietic growth factor.
• a vitamin D compound of the invention can be administered with an immunomodulator.
• a vitamin D compound of the invention can be administered with a cytotoxic agent.
• a vitamin D compound of the invention may be administered with an agent that affects RNA transcription.
• a vitamin D compound of the invention can be administered with a derivative of vitamin A, E, or K.
• a vitamin D compound of the invention can be administered with an agent that specifically binds biological targets related to MDS.
• a vitamin D compound of the invention can be administered with a signal transduction inhibitor.
• a vitamin D compound of the invention can be admimstered with an aminothiol.
• a vitamin D compound of the invention can be administered with an arsenic- containing compound. Further embodiments of the invention encompass administration of vitamin D compound of the invention in conjunction with more than one ofthe active agents described herein.
• a vitamin D compound of the invention can be administered with a growth factor.
• Any growth factor known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof, may be administered with a vitamin D compound to a subject in need of such administration.
• one or more growth factor(s) known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered with a vitamin D compound and one or more additional active agent(s) as described herein.
• growth factors examples include, without limitation, cytokines or hematopoietic growth factors such as, e.g., EPO, TPO, GM-CSF, G-CSF, IFN-alpha, IL-1, IL-2, IL-3, IL-6, IL-8, IL-11, and IL-12.
• cytokines or hematopoietic growth factors such as, e.g., EPO, TPO, GM-CSF, G-CSF, IFN-alpha, IL-1, IL-2, IL-3, IL-6, IL-8, IL-11, and IL-12.
• recombinant, modified, mimetic, fragmentary, or analogous forms of the above described cytokines or hematopoietic growth factors may also be used in the various embodiments of the invention. See, e.g., U.S. Patent Nos.
• cytokines or hematopoietic growth factors include r-HuEPO and r-mefHuG-CSF.
• EPOGEN® An example of a commercial form of r-HuEPO is EPOGEN®, which is produced by recombinant DNA technology and has the same biological effects and the same amino acid sequence as endogenous erythropoietin.
• a 1 ml dosage form of EPOGEN® can contain 2000, 3000, 4000, or 10,000 Units of epoetin alfa, 2.5 mg albumin (human), 1.2 mg sodium phosphate monobasic monohydrate, 1.8 mg sodium phosphate dibasic anhydrate, 0.7 mg sodium citrate, 5.8 mg sodium chloride, and 6.8 mg of citric acid, in water for injection, USP (pH 6.9 ⁇ 0.3).
• Multidose forms of EPOGEN® are available, and all dosage forms are in vials for parenteral administration. See Physicians' Desk Reference 582 (56th ed., 2002).
• NEUPOGEN® An example of a commercial form of r-mefHuG-CSF, also known as filgrastim, is NEUPOGEN®, which is produced by recombinant DNA technology in E. coli and differs from G-CSF isolated from human cells in that it is not glycosylated.
• a 1 ml dosage form of NEUPOGEN® can contain 300 ⁇ g of filgrastim, 0.59 mg Acetate, 50.0 mg Sorbitol, 0.004% TWEEN® 80, 0.035 mg Sodium and 1.0 mL Water for Injection, USP. Larger dosage forms of NEUPOGEN® are available, and all dosage forms are in vials for parenteral administration. See Id. at 588.
• a vitamin D compound of the invention can be administered with an immunomodulator.
• the immunomodulator can be any immunomodulator known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof.
• one or more immunomodulator(s) known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) described herein.
• immunomodulators examples include, without limitation, anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), thalidomide, prednisone, cyclosporin A (CyA), dexamethasone, and pentoxifylline.
• ATG anti-thymocyte globulin
• ALG anti-lymphocyte globulin
• thalidomide thalidomide
• prednisone prednisone
• CyA cyclosporin A
• dexamethasone dexamethasone
• pentoxifylline examples include, without limitation, anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), thalidomide, prednisone, cyclosporin A (CyA), dexamethasone, and pentoxifylline.
• a vitamin D compound of the invention can be administered with a cytotoxic agent.
• the cytotoxic agent can be any cytotoxic agent known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof.
• one or more cytotoxic agent(s) known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) as described herein.
• any cytotoxic agent can be employed according to the methods of the invention; many cytotoxic agents suitable for chemotherapy of MDS or cancer in general are known in the art.
• the cytotoxic agent can be an anti- metabolite (e.g., 5-flourouricil (5-FU), methotrexate (MTX), fludarabine, etc.), an anti-microtubule agent (e.g., vincristine; vinblastine; taxanes such as paclitaxel and docetaxel; etc.), an alkylating agent (e.g., cyclophosphamide, melphalan, bischloroethylnitrosurea, etc.), platinum agents (e.g., cisplatin, carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyc lines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin-
• cytotoxic agents that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits of the invention, include, without limitation, cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel, and cyclophosphamide.
• a vitamin D compound of the invention can be administered with an agent that affects RNA transcription.
• the agent that affects RNA transcription can be any agent that affects RNA transcription known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof.
• one or more agent(s) that affect RNA transcription known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) as described herein.
• Non-limiting examples of an agent that affects RNA transcription include decitabine, 5- azacytidine, depsipep tides, and phenylbutyrate.
• a vitamin D compound of the invention can be administered with a derivative of vitamin A, E, or K.
• the derivative of vitamin A, E, or K can be any derivative of vitamin A, E, or K known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof
• one or more derivative(s) of vitamin A, E, or K known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) as described herein.
• Non-limiting examples of a derivative of vitamin A, E, or K that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits of the invention, include all trans retinoic acid, 13-cis-retinoic acid, tocopherol, and menatetrenone.
• a vitamin D compound ofthe invention can be administered with an agent that specifically binds biological targets related to MDS.
• the agent that specifically binds biological targets related to MDS can be any agent that specifically binds biological targets related to MDS known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof.
• one or more agent(s) that specifically bind biological targets related to MDS known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) as described herein.
• Non-limiting examples of an agent that specifically binds biological targets related to MDS that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits of the invention, include anti-VEGF, gemtuzumab ozogamicin, and TNFR:Fc.
• a vitamin D compound ofthe invention can be administered with a signal transduction inhibitor.
• the signal transduction inhibitor can be any signal transduction inhibitor known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof.
• one or more signal transduction inhibitor(s) known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) as described herein.
• Non-limiting examples of such signal transduction inhibitors that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits of the invention, include famesyl transferase inhibitors such as, e.g. ZA NESTRATM and SARASARTM and tyrosine kinase inhibitors such as, e.g., SU5416, SU6668, and PTK787/ZK222584.
• famesyl transferase inhibitors such as, e.g. ZA NESTRATM and SARASARTM
• tyrosine kinase inhibitors such as, e.g., SU5416, SU6668, and PTK787/ZK222584.
• a vitamin D compound ofthe invention can be administered with an aminothiol.
• the aminothiol can be any aminothiol known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof.
• one or more aminothiol(s) known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) as described herein.
• a non-limiting example of an aminothiol that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits ofthe invention, is amifostine.
• a vitamin D compound ofthe invention can be administered with an arsenic-containing compound.
• the arsenic-containing compound can be any arsenic-containing compound known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof.
• one or more arsenic-containing compound(s) known by one of skill in the art to be effective to treat MDS, or ameliorate a symptom thereof may be administered to a subject with a vitamin D compound and one or more additional active agent(s) as described herein.
• a non- limiting example of an arsenic-containing compound that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits ofthe invention, is arsenic trioxide.
• the invention provides methods of treating MDS, or ameliorating a symptom thereof, in a subject in need of such treatment or amelioration. It further encompasses methods of treating subjects who have been previously treated for MDS, as well as those who have not previously been treated for MDS. Because subjects with MDS have heterogeneous clinical manifestations and varying clinical outcome, it has become apparent that staging the subjects according to their prognosis and approaching therapy depending on the severity and stage is necessary.
• the methods of this invention can be used in various stages of treatments for subjects with one or more types of MDS including but not limited to refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMML).
• RA refractory anemia
• RARS ringed sideroblasts
• RAEB RA with excess blasts
• RAEB-T RAEB in transformation
• CMML chronic myelomonocytic leukemia
• the methods of the invention can be used to in various stages of treatments for subjects with one or more types of MDS including but not limited to low risk, intermediate- 1 risk, intermediate-2 risk, or high risk MDS.
• the present invention provides methods for administering therapeutically effective doses of vitamin D compounds while minimizing the risk of hypercalcemia for the treatment of myelodysplastic syndromes, or amelioration of a symptom thereof.
• the methods comprise administering a therapeutically effective dose of vitamin D compounds in the treatment of MDS, or amelioration of a symptom thereof.
• the methods incorporate administering the vitamin D compounds intermittently in high doses. Intermittent administration of the vitamin D compounds allows the high doses to be administered to a subject while minimizing or eliminating hypercalcemia.
• the methods incorporate the use of oral vitamin D compound formulations.
• the methods incorporate the use of stable, oral vitamin D compound formulations with improved bioavailabihty and rapid onset of peak blood levels of vitamin D compounds.
• the methods incorporate the use of oral vitamin D compound formulations in the form of an emulsion pre-concentrate.
• the methods incorporate the use of intravenous (i.v.) vitamin D compound formulations.
• the vitamin D compounds are administered as a monotherapy.
• the vitamin D compounds and formulations are administered in combination with one or more additional active agents.
• the vitamin D compounds and formulations are administered in combination with one or more hematopoietic growth factors or cytokines.
• the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds while minimizing the risk of hypercalcemia for the treatment of myelodysplastic syndromes, or amelioration of a symptom thereof.
• the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds for the treatment of anemia associated with MDS.
• the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to increase plasma hemoglobin concentrations of a subject with MDS.
• the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to reduce transfusion requirements of a subject with MDS.
• the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds for the treatment of thrombocytopenia associated with MDS. In yet other embodiments, the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to reduce the fatigue of a subject with MDS. In still other embodiments, the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to decrease the frequency and severity of bruising of a subject with MDS. In yet other embodiments, the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to reduce the frequency and severity of bleeding episodes of a subject with MDS.
• the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to reduce the frequency and severity of fevers suffered by a subject with MDS. In still other embodiments, the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds for the treatment of neutropenia associated with MDS. In still other embodiments, the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to reduce the frequency and severity of infections in a subject with MDS. In yet other embodiments, the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to delay the progression of MDS to leukemia in a subject with MDS.
• the methods of the invention encompass administering a therapeutically effective dose of vitamin D compounds to extend the survival of a subject with MDS.
• vitamin D compounds and other therapeutic agents effective to treat MDS can act in complementary or synergistic ways in the treatment of MDS, or amelioration of a symptom thereof.
• one embodiment of the invention encompasses a method of treating MDS, or ameliorating a symptom thereof, which comprises administering to a patient in need of such treatment and/or amelioration a therapeutically effective dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof and a therapeutically effective dose of one or more additional active agent(s) as described herein.
• High systemic levels of vitamin D compounds can be achieved without the onset of hypercalcemia by intermittently administering the vitamin D compounds according to the methods of the invention.
• High doses of vitamin D compounds include doses greater than about 3 ⁇ g as discussed in the sections below. Therefore, in certain embodiments of the invention, the methods for the treatment of MDS, or amelioration of a symptom thereof, encompass intermittently administering high doses of vitamin D compounds.
• High doses of vitamin D compounds can be administered before, concurrently with, after, or in cycles with other therapies, including but not limited to pharmacotherapy.
• the administration of vitamin D compounds can also occur in cycling regimens such that administration of the vitamin D compound can occur before, concurrently with, after, or in any cycling regimen with other treatments within a cycling series of such treatments.
• the frequency of the intermittent administration can be limited by a number of factors including but not limited to the pharmacokinetic parameters of the compound or formulation and the pharmacodynamic effects of the vitamin D compound on the subject. For example, subjects with MDS having impaired renal function may require less frequent administration of the vitamin D compounds because of those subjects' decreased ability to excrete calcium. [0091] The following is exemplary only and merely serves to illustrate that the term "intermittent" can encompass any administration regimen designed by a person of ordinary skill in the art.
• the vitamin D compound can be administered not more than once every three days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects ofthe vitamin D compound on the subject.
• the vitamin D compound can be administered not more than once every four days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject.
• the vitamin D compound can be administered not more than once every five days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject.
• the vitamin D compound can be administered not more than once every six days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject.
• the vitamin D compound can be administered not more than once every seven days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject.
• the vitamin D compound can be administered not more than once every eight days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject.
• the vitamin D compound can be administered not more than once every nine days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject.
• the vitamin D compound can be administered not more than once every ten days.
• the administration can continue for one, two, three, or four weeks or one, two, three, four, five, or six months, or one year, or longer.
• the vitamin D compound can be administered until the anemia associated with MDS is ameliorated.
• the vitamin D compound can be administered under the same or different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject.
• the vitamin D compound can be administered once per week for three months.
• the vitamin D compound can be administered under the same or different schedule.
• the period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects ofthe vitamin D compound on the subject.
• the vitamin D compound can be administered once every three weeks for a year.
• the vitamin D compound can be administered under the same or different schedule.
• the period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects ofthe vitamin D compound on the subject.
• the vitamin D compound can be administered once per week for 3 weeks out of each 4 week cycle. After a one week period of rest, the vitamin D compound can be administered under the same or different schedule.
• a therapeutically effective dose of a pharmaceutical agent in the acute or chronic management of a disease or disorder may vary depending on factors including, but not limited to, the disease or disorder treated, the specific pharmaceutical agents and the route of administration.
• a therapeutically effective dose of a vitamin D compound is any dose of the vitamin D compound effective to treat MDS or ameliorate a symptom thereof.
• a high dose of a vitamin D compound can be a dose from about 3 ⁇ g to about 300 ⁇ g or any dose within this range as discussed below.
• the dose, dose frequency, duration, or any combination may also vary according to age, body weight, response, and the past medical history of the subject as well as the route of administration, pharmacokinetic and pharmacodynamic effects of the pharmaceutical agent. These factors are routinely considered by one of skill in the art.
• vitamin D compounds are affected by a variety of factors that are well-known to persons of ordinary skill in the art. As discussed above, the pharmacokinetic properties of vitamin D compounds limit the peak concentration of vitamin D compounds that can be obtained in the blood without inducing the onset of hypercalcemia and preferably without inducing the onset of clinical hypercalcemia. The rate and extent of abso ⁇ tion, distribution, binding or localization in tissues, biotransformation and excretion of the vitamin D compound can all affect the frequency at which the pharmaceutical agent can be administered. In certain embodiments, vitamin D compounds are administered intermittently in high doses as a method of treating MDS, or ameliorating a symptom thereof, according to the dosing schedule described above.
• the methods comprise administering a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 ⁇ g, or any range of doses therein.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 0.12 ⁇ g/kg to about 3 ⁇ g/kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 3 ⁇ g to about 300 ⁇ g.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 5 ⁇ g to about 200 ⁇ g. In still other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 5 ⁇ g to about 105 ⁇ g.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 15 ⁇ g to about 105 ⁇ g. In yet other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 15 ⁇ g to about 90 ⁇ g.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 20 ⁇ g to about 80 ⁇ g. In yet other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 30 ⁇ g to about 60 ⁇ g.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 30 ⁇ g to about 75 ⁇ g.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of about 45 ⁇ g.
• these standard doses are for an average sized adult of approximately 70 kg and can be adjusted for the factors routinely considered as stated above.
• the dose of the vitamin D compounds of up to 105 ⁇ g may be administered without substantially increasing the half-life and associated toxicity of the vitamin D compounds. Therefore, in a preferred embodiment, the dose ofthe vitamin D compound is 105 ⁇ g or less.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations of the vitamin D compound from about 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM.
• the methods ofthe invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations of the vitamin D compound exceeding about 0.5 nM.
• methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations of the vitamin D compound from about 0.5 nM to about 20 nM.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations of the vitamin D compound from about 1 nM to about 10 nM.
• methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations of the vitamin D compound from about 1 nM to about 7 nM.
• methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations of the vitamin D compound from about 3 nM to about 7 nM.
• methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations of the vitamin D compound from about 5 nM to about 7 nM.
• methods ofthe invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose that achieves peak plasma concentrations ofthe vitamin D compound from about 3 nM to about 5 nM.
• the methods of the invention further comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof that achieves peak plasma concentrations rapidly, e.g., within four hours.
• the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof that is eliminated quickly, e.g., with an elimination half-life of less than 12 hours.
• the methods of the invention encompass intermittently administering high doses of vitamin D compounds to a subject with MDS and monitoring the subject for symptoms associated with hypercalcemia.
• the methods of the invention encompass intermittently administering high doses of vitamin D compounds to a subject with MDS and monitoring the renal function ofthe subject.
• the methods of the invention encompass intermittently administering high doses of vitamin D compounds to a subject with MDS and monitoring the subject for calcification of soft tissues, such as, for example, cardiac tissue.
• the methods of the invention encompass intermittently administering high doses of vitamin D compounds to a subject with MDS and monitoring the subject for increased bone density.
• the methods of the invention encompass intermittently administering high doses of vitamin D compounds to a subject with MDS and monitoring the subject for hypercalcemic nephropathy. In still other embodiments, the methods of the invention encompass intermittently administering high doses of vitamin D compounds to a subject with MDS and monitoring the blood calcium concentration ofthe subject to ensure that the blood calcium concentration is less than about 10.5 mg/dL.
• high blood levels of vitamin D compounds can be safely obtained in conjunction with reducing the transport of calcium into the blood.
• higher 1,25-dihydroxyvitamin D concentrations are safely obtainable without the onset of hypercalcemia when administered in conjunction with a reduced calcium diet.
• the calcium can be trapped by an adsorbent, absorbent, ligand, chelate, or other binding moiety that cannot be transported into the blood through the small intestine.
• the rate of osteoclast activation can be inhibited by administering, for example, a bisphosphonate such as, e.g., pamidronate, or ZOMETA (Novartis Pharmaceuticals Co ⁇ ., East Hanover, NJ) in conjunction with the vitamin D compound.
• a bisphosphonate such as, e.g., pamidronate, or ZOMETA (Novartis Pharmaceuticals Co ⁇ ., East Hanover, NJ) in conjunction with the vitamin D compound.
• high blood levels of vitamin D compounds are safely obtained in conjunction with maximizing the rate of clearance of calcium.
• calcium excretion can be increased by ensuring adequate hydration and salt intake.
• diuretic therapy can be used to increase calcium excretion.
• the methods of the present invention also provide combination therapies comprising administering one or more vitamin D compounds in combination with one or more additional active agents that are not vitamin D compounds.
• the additional active agents can be any agents that have a therapeutic effect to treat MDS, or ameliorate a symptom thereof, that are known to one of skill in the art without limitation.
• the combination therapies of the present invention comprise administering one or more additional active agents which improve the therapeutic or ameliorative effects of the vitamin D compounds by producing an additive or synergistic effect.
• the combination therapies are advantageously utilized for the treatment of MDS, or amelioration of a symptom thereof.
• the one or more vitamin D compounds may be administered prior to (e.g., 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 5 days, 1 week, 2 weeks, 1 month or more before), after (e.g., 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 5 days, 1 week, 2 weeks, 1 month or more after), concurrently with, or in any cycling regimen involving the administration of one or more additional active agents.
• the additional active agents are administered less often than the vitamin D compounds
• the one or more vitamin D compounds are preferably administered about one day before the one or more additional active agents.
• the additional active agents that are not vitamin D compounds can be one or more growth factors.
• the growth factors can be administered before, concurrently with, after, or in cycles with a vitamin D compound in the methods of the present invention to benefit from the ability of the vitamin D compound to sensitize cells to the actions of the growth factors.
• less growth factor may be used in the treatment of MDS, or amelioration of a symptom thereof.
• cycling therapy is used to inhibit the development of resistance or reduce the resistance to one or more ofthe therapies, avoid or reduce the side effects of the therapies, and/or improve the effectiveness ofthe treatments.
• the one or more growth factors can be cytokines.
• the cytokines can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention.
• the one or more growth factors can be hematopoietic growth factors.
• the hematopoietic growth factors can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods ofthe present invention.
• the hematopoietic growth factor administered before, concurrently with, after, or in cycles with a vitamin D compound can be EPO, e.g., r-HuEPO, or a pharmacologically active mutant or derivative thereof.
• the hematopoietic growth factor that can be administered before, concurrently with, after, or in cycles with a vitamin D compound can be G-CSF, e.g., r-metHuG-CSF, or a pharmacologically active mutant or derivative thereof.
• the hematopoietic growth factors that can be administered before, concurrently with, after, or in cycles with a vitamin D compound can be a combination of EPO and HuG-CSF, or pharmacologically active mutants or derivatives thereof.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with EPO, G-CSF, a pharmacologically active mutant or derivative thereof, or a combination thereof
• the range of r-HuEPO, or a pharmacologically active mutant or derivative thereof, administered to a subject to treat MDS, or ameliorate a symptom thereof can be from about 1 Unit/kg to about 2000 Units/kg three times per week (TIW), preferably from about 10 Units/kg to about 1000 Units/kg TIW, and more preferably from about 25 Units/kg to about 500 Units/kg TIW.
• TIW three times per week
• the r-HuEPO can be administered to a subject to treat MDS, or ameliorate a symptom thereof, in a dose of about 1, 10, 20, 50, 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 1750, 2000 Units/kg or any range of doses therein.
• the r-HuEPO can be administered in combination with one or more vitamin D compounds, wherein the one or more vitamin D compounds are administered according to the doses and schedules described herein.
• the range of r-metHuG-CSF, or a pharmacologically active mutant or derivative thereof, administered to a subject to treat MDS, or ameliorate a symptom thereof can be from about 1 ⁇ g/kg/day to about 100 ⁇ g/kg/day, preferably from about 3 ⁇ g/kg/day to about 75 ⁇ g/kg/day, and more preferably from about 5 ⁇ g/kg/day to about 50 ⁇ g/kg/day.
• the r-metHuG-CSF can be administered to a subject to treat MDS, or ameliorate a symptom thereof, in a dose of about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 ⁇ g/kg or any range of doses therein.
• the r- metHuG- CSF, or a pharmacologically active mutant or derivative thereof can be administered in combination with one or more vitamin D compounds, wherein the one or more vitamin D compounds are administered according to the doses and schedules described herein.
• a vitamin D compound can be administered in combination with r-HuEPO, r-metHuG-CSF, a pharmacologically active mutant or derivative thereof, or a combination thereof, wherein r-HuEPO, r-metHuG- CSF, or their pharmacologically active mutants or derivatives are administered in the above described doses, respectively.
• the hematopoietic growth factor is r-HuEPO and is administered before, concurrently with, after, or in cycles with the administration of a vitamin D compound, wherein the range of administration of r-HuEPO is from about 50 Units/kg to about 100 Units/kg TIW.
• the hematopoietic growth factor is r- metHuG-CSF and is administered before, concurrently with, after, or in cycles with a vitamin D compound, wherein the range of administration of r-metHuG-CSF is from about 5 ⁇ g/kg/day to about 25 ⁇ g/kg/day.
• the hematopoietic growth factors are a combination of r-HuEPO and r-metHuG-CSF and are administered before, concurrently with, after, or in cycles with a vitamin D compound, wherein the range of administration is from about 25 Units/kg to about 500 Units/kg TIW for r-HuEPO and from about 5 ⁇ g/kg/day to about 25 ⁇ g/kg/day for r-metHuG-CSF.
• the growth factor administered before, concurrently with, after, or in cycles with a vitamin D compound can be one of IL-1, IL-2, IL- 3, IL-4, IL-6, IL-8, IL-11, IL-12, IFN-alpha, GM-CSF, TPO, or a pharmacologically active mutant or derivative thereof.
• the growth factors administered before, concurrently with, after, or in cycles with a vitamin D compound can be more than one of IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-11, IL-12, IFN-alpha, GM-CSF, TPO, or a pharmacologically active mutant or derivative thereof.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of r-HuEPO, r-mefHuG-CSF, IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-11, IL-12, IFN-alpha, GM-CSF, TPO, a pharmacologically active mutant or derivative thereof, or a combination thereof.
• the additional active agents that are not vitamin D compounds can be immunomodulators.
• the immunomodulators can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention.
• the immunomodulator can be one of ATG, ALG, thalidomide, prednisone, CyA, dexamethasone, or pentoxifylline.
• the immunomodulators can be more than one of ATG, ALG, thalidomide, prednisone, CyA, dexamethasone, or pentoxifylline.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of ATG, ALG, thalidomide, prednisone, CyA, dexamethasone, or pentoxifylline, or a combination thereof.
• the immunomodulator is ATG, wherein the range of administration of ATG is from about 10 mg/kg/day to about 100 mg/kg/day. In a preferred embodiment, the immunomodulator is ATG, wherein the range of administration of ATG is from about 35 mg/kg/day to about 45 mg/kg/day.
• the immunomodulator is thalidomide, wherein the range of administration of thalidomide is from about 50 mg/day to about 500 mg/day. In a preferred embodiment, the immunomodulator is thalidomide, wherein the range of administration of thalidomide is from about 100 mg/day to about 400 mg/day.
• the additional active agents that are not vitamin D compounds can be cytotoxic agents.
• the cytotoxic agents can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention.
• the cytotoxic agent can be an antimetabolite, an anti- microtubule agent, an alkylating agent, a platinum agent, an anthracycline, an antibiotic agent, or a topoisomerase inhibitor.
• the cytotoxic agents can be more than one of an antimetabolite, an anti-microtubule agent, an alkylating agent, a platinum agent, an anthracycline, an antibiotic agent, or a topoisomerase inhibitor.
• the vitamin D compound can be administered as an emulsion pre- concentrate in combination with one or more than one of an antimetabolite, an anti-microtubule agent, an alkylating agent, a platinum agent, an anthracycline, an antibiotic agent, or a topoisomerase inhibitor, or a combination thereof.
• the cytotoxic agent can be one of cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel, or cyclophosphamide.
• the cytotoxic agents can be more than one of cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel, or cyclophosphamide.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel, or cyclophosphamide, or a combination thereof.
• the cytotoxic agent is cytarabine, wherein the range of administration of cytarabine is from about 10 mg/m 2 /day to about 1 g/m 2 /day. In a preferred embodiment, the cytotoxic agent is cytarabine, wherein the range of administration of cytarabine is from about 5 mg/m 2 /day to about 20 mg/m 2 /day. In another particular embodiment, the cytotoxic agent is idarubicin, wherein the range of administration of idarubicin is from about 9 mg/m 2 /day to about 18 mg/m 2 /day.
• the cytotoxic agent is melphalan, wherein the range of administration of melphalan is from about 1 mg/day to about 100 mg/day. In a preferred embodiment, the cytotoxic agent is melphalan, wherein the range of administration of melphalan is from about 1 mg/day to about 5 mg/day. In still another specific embodiment, the cytotoxic agent is topotecan, wherein the range of administration of topotecan is from about 1 mg/m /day to about 100 rag/m /day. In a preferred embodiment, the cytotoxic agent is topotecan, wherein the range of administration of topotecan is from about 1 mg/m /day to about 5 mg/m 2 /day.
• D compounds can be one or more agents that affect RNA transcription.
• the agents that affect RNA transcription can be administered before, concurrently with, after, or in cycles with a vitamin D compound in accordance with the methods of the present invention.
• the agent that affects RNA transcription can be one of decitabine, 5-azacytidine, depsipeptides, or phenylbutyrate.
• the agents that affect RNA transcription can be more than one of decitabine, 5-azacytidine, depsipeptides, or phenylbutyrate.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of decitabine, 5-azacytidine, or depsipeptides, or a combination thereof.
• the agent that affects RNA transcription is decitabine, wherein the range of administration of decitabine is from about 10 mg/m 2 /day to about 200 mg/m 2 /day. In a preferred embodiment, the agent that affects RNA transcription is decitabine, wherein the range of administration of decitabine is from about 45 mg/m 2 /day to about 100 mg/m 2 /day. In another specific embodiment, the agent that affects RNA transcription is 5-azacytidine, wherein the range of administration of 5-azacytidine is from about 5 mg/m 2 /day to about 200 mg/m 2 /day. In a preferred embodiment, the agent that affects RNA transcription is 5-azacytidine, wherein the range of administration of 5- azacytidine is from about 10 mg/m 2 /day to about 75 mg/m 2 /day.
• the additional active agents that are not vitamin D compounds can be derivatives of vitamin A, E, or K.
• the derivatives of vitamin A, E, or K can be administered before, concurrently with, after, or in cycles with a vitamin D compound in accordance with the methods of the present invention.
• the derivative of vitamin A, E, or K can be one of ATRA, 13-cw-retinoic acid, tocopherol, or menatetrenone.
• the derivatives of vitamin A, E, or K can be more than one of ATRA, 13-cw-retinoic acid, tocopherol, or menatetrenone.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of ATRA, 13-ct-.-retinoic acid, tocopherol, or menatetrenone, or a combination thereof.
• the derivative of vitamin A, E, or K is ATRA, wherein the range of administration of ATRA is from about 10 mg/m 2 /day to about 200 mg/m 2 /day. In a preferred embodiment, the derivative of vitamin A, E, or K is ATRA, wherein the range of administration of ATRA is from about 25 mg/m 2 /day to about 80 mg/m 2 /day. In another specific embodiment, the derivative of vitamin A, E, or K is 13-c/_.-retinoic acid, wherein the range of administration of 13-ct.s-retinoic acid is from about 5 mg/m 2 /day to about 200 mg/m 2 /day.
• the derivative of vitamin A, E, or K is 13-c._.-retinoic acid, wherein the range of administration of 13-cw-retinoic acid is from about 10 mg/m 2 /day to about 100 mg/m 2 /day.
• the derivative of vitamin A, E, or K is menatetrenone, wherein the range of administration of menatetrenone is from about 5 mg/day to about 200 mg/day.
• the derivative of vitamin A, E, or K is menatetrenone, wherein the range of administration of menatetrenone is from about 10 mg/day to about 100 mg/day.
• the derivative of vitamin A, E, or K is tocopherol, wherein the range of administration of tocopherol is from about 400 IU/day to about 3000 IU/day. In a preferred embodiment, the derivative of vitamin A, E, or K is tocopherol, wherein the range of administration of tocopherol is from about 800 IU/day to about 2000 IU/day.
• the additional active agents that are not vitamin D compounds can be agents that specifically bind biological targets related to MDS.
• the agents that specifically bind biological targets related to MDS can be administered before, concurrently with, after, or in cycles with a vitamin D compound in accordance with the methods of the present invention.
• the agent that specifically binds biological targets related to MDS can be one of anti-VEGF, gemtuzumab ozogamicin, or TNFR:Fc.
• the agents that specifically bind biological targets related to MDS can be more than one of anti-VEGF, gemtuzumab ozogamicin, or TNFR:Fc.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of anti-VEGF, gemtuzumab ozogamicin, or TNFR:Fc, or a combination thereof
• the agent that specifically binds biological targets related to MDS is gemtuzumab ozogamicin, wherein the range of administration of gemtuzumab ozogamicin is from about 5 mg/m /week to about 20 mg/m /week.
• the additional active agents that are not vitamin D compounds can be signal transduction inhibitors.
• the signal transduction inhibitors can be administered before, concurrently with, after, or in cycles with a vitamin D compound in accordance with the methods ofthe present invention.
• the signal transduction inhibitors can be one or more farnesyl transferase inhibitor(s).
• the farnesyl transferase inhibitor can be one of ZARNESTRATM and SARASARTM.
• the farnesyl transferase inhibitor can be more than one of ZARNESTRATM and SARASARTM.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of ZARNESTRATM and SARASARTM, or a combination thereof.
• the signal transduction inhibitors can be tyrosine kinase inhibitors.
• the tyrosine kinase inhibitors can be administered before, concurrently with, after, or in cycles with a vitamin D compound in accordance with the methods of the present invention.
• the tyrosine kinase inhibitor can be one of SU5416, SU6668, or PTK787/ZK222584.
• the tyrosine kinase inhibitors can be more than one of SU5416, SU6668, or PTK787/ZK222584.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with one or more of SU5416, SU6668, PTK787/ZK222584, or a combination thereof.
• the additional active agents that are not vitamin D compounds can be aminothiols.
• the aminothiols can be administered before, concurrently with, after, or in cycles with a vitamin D compound in accordance with the methods of the present invention.
• the aminothiol is amifostine.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with amifostine.
• the aminothiol is amifostine, wherein the range of administration of amifostine is from about 50 mg/m 2 /day to about 600 mg/m 2 /day when administered over multiple days, or from about 600 mg/m to about 1.2 g/m when administered in a single dose.
• the aminothiol is amifostine, wherein the range of administration of amifostine is from about 100 mg/m 2 /day to about 400 mg/m 2 /day when administered over multiple days, or from about 740 mg/m 2 to about 910 mg/m 2 when administered in a single dose.
• D compounds can be arsenic-containing compounds.
• the arsenic-containing compounds can be administered before, concurrently with, after, or in cycles with a vitamin D compound in accordance with the methods of the present invention.
• the arsenic- containing compound is arsenic trioxide.
• the vitamin D compound can be administered as an emulsion pre-concentrate in combination with arsenic trioxide.
• the doses, dose frequencies, and durations of administration of any combination stated above may also vary according to age, body weight, response, and the past medical history of the subject as well as the route of administration, pharmacokinetic and pharmacodynamic effects of the pharmaceutical agent. These factors are routinely considered by one of skill in the art. Examples of other dosage schedules and the factors considered by one of skill in the art when designing a dosage schedule are discussed above.
• the vitamin D compound can be administered by any method known to those of skill in the art.
• the vitamin D compounds can be administered by any route known to one of skill in the art that can achieve rapid onset of peak plasma concentrations of the vitamin D compounds.
• the vitamin D compounds are administered orally, mucosally, or parenterally.
• mucosal administration of the vitamin D compounds can include nasal, sublingual, vaginal, buccal, or rectal administration
• parenteral administration of the vitamin D compounds can include intravenous, intramuscular, or intraarterial administration.
• the vitamin D compound may be administered as either a bolus injection or as an infusion over several minutes to hours.
• the vitamin D compounds can be administered either orally or intravenously.
• the timing of the administration of the vitamin D compound can also vary.
• the vitamin D compound can be administered, regardless of the dosage form, as co-therapy either before, concurrently with, after, or in cycles with administration one or more additional active agent(s).
• the administration of the vitamin D compounds and formulations can also occur in a cycling treatment regimen such as the administration ofthe vitamin D between or concurrently with other treatments within a cycling series of these other treatments.
• the vitamin D compounds can be administered intermittently according to continuous or non-continuous periodic schedules.
• the additional active agents may be administered by any method known to one of skill in the art.
• the pharmaceutical agent can comprise one or more vitamin D compounds or optionally one or more vitamin D compounds in combination with one or more additional active agents.
• the pharmaceutical agent can be administered in combination with one or more additional active agents as well, such as hematopoietic growth factors or cytokines in the treatment of MDS.
• the pharmaceutical agent can be in the form of any pharmaceutical formulation known to those of skill in the art.
• the pharmaceutical formulations and dosage forms of the present invention comprise at least one vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
• the pharmaceutical formulations and dosage forms of the invention can further comprise one or more excipients, diluents or any other components known to persons of skill in the art and germane to the methods of formulation of the present invention.
• the pharmaceutical formulations and dosage forms of the present invention can further comprise other active ingredients that are not vitamin D compounds.
• the pharmaceutical formulations of the present invention can be used to prepare single unit dosage forms.
• composition, shape and type of dosage forms may typically vary depending on their use.
• a dosage form used in the acute treatment of a disease may comprise larger amounts of pharmaceutical agents than a dosage form used in the chronic treatment of the same disease.
• a parenteral dosage form may contain smaller amounts of pharmaceutical agents than an oral dosage form used to treat the same disease.
• the dosage forms are suitable for oral; mucosal such as nasal, sublingual, vaginal, buccal, or rectal; or parenteral such as intravenous, intramuscular, or intraarterial administration.
• parenteral such as intravenous, intramuscular, or intraarterial administration.
• the vitamin D compound may be administered as either a bolus injection or as an infusion over several minutes to hours.
• dosage forms include but are not limited to tablets, caplets, capsules such as hard and soft gelatin capsules, cachets, troches, lozenges, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters, solutions, patches, aerosols such as nasal sprays or inhalers, and gels.
• Suitable liquid dosage forms for oral or mucosal administration include but are not limited to aqueous and non-aqueous liquid suspensions, oil-in-water emulsions, water-in-oil emulsions, solutions and elixirs.
• Liquid dosages include but are not limited to the reconstitution of sterile solids, which can be crystalline or amo ⁇ hous, into liquid dosage forms suitable for parenteral administration.
• Preferred dosage forms of the present invention include oral dosage forms and intravenous dosage forms.
• the vitamin D compounds are administered intermittently orally, the vitamin D compounds are preferably administered in the form of emulsion pre- concentrates.
• the oral dosage form is an emulsion pre- concentrate of a vitamin D compound that comprises about 15 ⁇ g of calcitriol in addition to the following excipients with the amount given in approximate percentage by weight: 65% Miglyol 812N ® , 30% Gelucire 44/14 ® , 5% vitamin-E TPGS and about 0.05% each of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
• BHT butylated hydroxytoluene
• BHA butylated hydroxyanisole
• the intravenous dosage form is CALCUEX®, which can contain 1 ⁇ g calcitriol, 4 mg of Polysorbate 20, 2.5 mg of sodium ascorbate and optionally either HCI or NaOH for pH adjustment.
• Typical pharmaceutical formulations and dosage forms comprise one or more excipients.
• Suitable excipients are well-known to those skilled in the art and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for inco ⁇ oration into a pharmaceutical formulation or dosage form depends on a variety of factors well-known in the art including, but not limited to, the route by which the dosage form is administered.
• oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific pharmaceutical agent in the dosage form.
• the pharmaceutical formulations and dosage forms can be anhydrous, since water, as well as heat, can facilitate the degradation of some compounds.
• water, as well as heat can facilitate the degradation of some compounds.
• the effect of water as well as heat on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment and use of formulations.
• Anhydrous pharmaceutical formulations and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
• the anhydrous pharmaceutical formulations are prepared, stored and packaged to preserve the anhydrous environment by using materials capable of preventing exposure to water and facilitating the production of suitable formulary kits.
• suitable materials include but are not limited to hermetically sealed foils, plastics, and unit dose containers such as vials, blister packs and strip packs.
• the pharmaceutical formulations and dosage forms comprise one or more stabilizers, which are compounds that reduce the rate at which an active ingredient will decompose and include but are not limited to antioxidants such as ascorbic acid, pH buffers, or salt buffers.
• the pharmaceutical formulations of the present invention can be, for example, in a semisolid formulation or in a liquid formulation.
• Semisolid formulations ofthe present invention can be any semisolid formulation known by those of ordinary skill in the art, including, for example, gels, pastes, creams and ointments.
• the pharmaceutical formulations can comprise preparations of vitamin D compounds that are currently in clinical use.
• vitamin D compound preparations and analogs include but are not limited to dihydrotachysterol (DHTTM, Roxane; and HYTAKEROL ® , Sanofi Winthrop Pharm); calcitriol (ROCALTROL ® , Roche; and CALCUEX ® , Abbott); calcifediol (CALDEROL ® , Organon); ergocalciferol (CALCIFEROL ® , Schwarz Pharma; and DRISDOL ® , Sanofi Pharm); cholecalciferol (DELTA-D ® and vitamin D 3 , Freeda); paracalcitol (ZEMPLAR ® , Abbott); doxercalciferol (HECTOROL ® , Bone Care Int'l); and alfacalcidol (ALFAD ® and ONE-ALPHA ® ).
• ROCALTROL ® is a calcitriol formulation currently in clinical use and available as capsules containing 0.25 and 0.5 ⁇ g calcitriol and as an oral solution containing 1 ⁇ g/mL calcitriol.
• Dosage forms of ROCALTROL ® can contain additional components such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants.
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluene
• the capsules can also contain a fractionated triglyceride of coconut oil and the oral solution contains a fractionated triglyceride of palm seed oil. See Physicians' Desk Reference 2991 (56th ed., 2002).
• the pharmaceutical agents can be administered orally.
• Pharmaceutical formulations that are suitable for oral administration can be presented as discrete dosage forms including, but not limited to, tablets such as chewable tablets, caplets, capsules and liquids such as flavored syrups.
• Such dosage forms contain predetermined amounts of a pharmaceutical agent and may be prepared by methods of pharmacy well-known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
• Typical oral dosage forms are prepared by combining a pharmaceutical agent with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms.
• excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents.
• excipients suitable for use in solid oral dosage forms such as powders, tablets, capsules, and caplets include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents.
• suitable forms of binders include, but are not limited to, com starch, potato starch, other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives.
• cellulose derivatives include but are not limited to ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose.
• Other binders include but are not limited to polyvinyl pyrrolidone, methyl cellulose, pre- gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose and mixtures thereof.
• Suitable forms of microcrystalline cellulose include, but are not limited to, those commercially known as AviCEL ® , AviCEL-PH-101 ® , AVICEL-PH-103 ® , AviCEL RC-581 ® , Avicel-PH-105 ® (Avicel ® products are available from FMC Co ⁇ oration, American Viscose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof.
• the binder can be a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as Avicel RC-581 ® .
• Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ® and STARCH 1500 LM ® .
• suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch and mixtures thereof.
• the binder or filler is typically present from about 50 to about 99 percent by weight ofthe pharmaceutical formulation or dosage form.
• disintegrants may be used in the formulations to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions.
• the pharmaceutical formulations comprise from about 0.5 to about 15 percent by weight of disintegrant. In a preferred embodiment, the pharmaceutical formulations comprise from about 1 to about 5 percent by weight of disintegrant.
• suitable disintegrants include but are not limited to agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums and mixtures thereof.
• suitable lubricants include but are not limited to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, and hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil.
• suitable lubricants include but are not limited to zinc stearate, ethyl oleate, ethyl laureate, agar and mixtures thereof.
• suitable lubricants include but are not limited to a syloid silica gel such as Aerosil 200 (manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), Cab-O-SlL ® (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA) and mixtures thereof.
• a syloid silica gel such as Aerosil 200 (manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), Cab-O-SlL ® (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA) and mixtures thereof.
• lubricants are typically present in an amount of less than about 1 weight percent ofthe pharmaceutical formulations or dosage forms.
• the oral dosage form can be tablets and capsules.
• Tablets and capsules can comprise solid excipients and represent the most advantageous oral dosage unit forms due to their ease of delivery. Tablets can be coated by standard aqueous or nonaqueous techniques if desired.
• dosage forms can be prepared by any pharmaceutical method.
• pharmaceutical formulations and dosage forms are prepared by uniformly and intimately admixing the pharmaceutical agents with liquid carriers, finely divided solid carriers, or both and then shaping the product into the desired form.
• a tablet can be prepared by compression or molding.
• Compressed tablets can be prepared by compressing the pharmaceutical agents, and optionally excipients, in a suitable machine. Molded tablets can likewise be made by molding a mixture of the pharmaceutical agents, and optionally excipients, moistened with an inert liquid diluent in a suitable machine.
• the unit dosage form of the composition is a capsule, and the total quantity of ingredients preferably range from about 10 ⁇ L to about 1000 ⁇ L. In a preferred embodiment, the total quantity of ingredients present in the capsule ranges from about 100 ⁇ L to about 300 ⁇ L.
• the relative proportion of ingredients in the formulations may vary according to the particular type of composition, the particular function of ingredients, the particular ingredients and the desired physical characteristics of the product.
• a composition may be a free flowing liquid or a paste for topical use. Determination of workable proportions in any particular instance are within the capability of a person of ordinary skill in the art. All indicated proportions and relative weight ranges described below are indicative of preferred teachings and not intended to be limiting in any way.
• Calcitriol can be light-sensitive and especially prone to oxidation.
• calcitriol and other active vitamin D compounds are lipophilic, meaning that they are soluble in lipids and some organic solvents but only sparsely soluble in a polar medium such as water.
• a polar medium such as water.
• the dispersion of such compounds in aqueous solutions e.g. the gastric fluids of the stomach, is significantly limited.
• the pharmacokinetic parameters of currently available active vitamin D compound formulations are suboptimal.
• currently available active vitamin D compound formulations tend to exhibit substantial variability of abso ⁇ tion in the small intestine.
• vitamin D compounds can be formulated as emulsion pre-concentrates to improve stability, even at elevated temperatures, to improve pharmacokinetic parameters and to reduce the variability in abso ⁇ tion in the small intestine.
• the method provides dosage forms of active vitamin D compounds, such as calcitriol, in sufficiently high concentrations to permit convenient use.
• the dosage form is stable at a variety of temperatures and rapidly becomes a nanodispersion in polar mediums that include but are not limited to gastric fluids, while performing within required pharmacokinetic parameters.
• the emulsion pre-concentrates exhibit a maximum blood concentration of a vitamin D compound that is at least 1.5-2 times greater than the maximum blood concentration observed with ROCALTROL ® , an elimination half- life that is one half or less than the elimination half-life observed with ROCALTROL ® , and a time to maximum plasma concentration that is shorter than the time to maximum plasma concentration observed with ROCALTROL ® .
• These pharmacokinetic characteristics are beneficial in achieving high blood levels of vitamin D compounds without the onset of hypercalcemia and preferably without the onset of clinical hypercalcemia.
• the emulsion pre-concentrates form an emulsion upon dilution with a polar phase component such as a liquid or solution, i.e. polar medium, that includes but is not limited to water.
• a polar phase component such as a liquid or solution, i.e. polar medium
• the ratio of polar medium to emulsion pre-concentrate is preferably 1 :1 or greater.
• the ratio of water to composition can range from about 1 :1 to about 5000:1.
• the ratio of water to composition can be about 1 :1, 2:1, 3:1, 4:1, 5:1, 10:1, 200:1, 300:1, 500:1, 1000:1, or 5000:1, or any range of ratios therein. The skilled artisan can determine the appropriate ratio for the desired application.
• the emulsion can be a submicron droplet emulsion, wherein the submicron droplet emulsions possess one or more of the following characteristics: (1) spontaneous emulsion formation when the components are brought into contact despite the absence of an energy source such as heat, high shear or other substantial agitation, (2) thermodynamically stability and (3) a monophasic state.
• the droplets or particles within submicron droplet emulsions may have a variety of shapes including but not limited to spheres and liquid crystals with lamellar, hexagonal or isotropic symmetries.
• Submicron droplet emulsions comprise droplets or particles having an average diameter ranging generally from about 50 nm to about 1000 nm, preferably from about 100 nm to about 750 nm, and more preferably from about 200 nm to about 400 nm.
• the emulsion has an absorbance ranging from about 0.3 to about 15.0 at 400 nm upon dilution of the emulsion pre-concentrate with a polar medium such as water. In other embodiments, the emulsion has an absorbance ranging from about 0.3 to about 8.0 at 400 nm. In certain embodiments, the absorbance can range from about 0.4, 0.5, 0.6, 1.0, 1.2, 1.6, 2.0, 2.2, 2.4, 2.5, 3.0, or 4.0, or any range of absorbances therein at 400 nm.
• the emulsion is formed with a 100:1 dilution of water with the emulsion pre-concentrate and has an absorbance ranging from about 0.3 to about 4.0 at 400 nm.
• Methods for determining the absorbance of a liquid solution are well-known by those in the art. The skilled artisan will be able to ascertain and adjust the relative proportions of the ingredients of the emulsion pre- concentrates of the invention in order to obtain, upon dilution with a polar medium such as water, an emulsion having any particular absorbance encompassed within the scope ofthe invention.
• the emulsion pre-concentrates comprise (a) one or more lipophilic phase components, (b) one or more surfactants, and (c) one or more vitamin D compounds; wherein said composition is an emulsion pre- concentrate, which upon dilution with a polar medium such as water in, for example, a water-to-composition ratio of about 1 : 1 or more forms an emulsion having an absorbance of greater than 0.3 at 400 nm.
• the emulsion pre-concentrates may further comprise either one or more hydrophobic or a hydrophilic phase components.
• the vitamin D compounds of the emulsion pre-concentrates are described above.
• the vitamin D compounds can be active vitamin D compounds or compounds that can be converted to active vitamin D compounds when administered.
• the lipophilic phase components can be any pharmaceutically acceptable solvent which is not miscible with water.
• the lipophilic phase component comprises mono-, di- or triglycerides that include but are not limited to those derived from C 6 , C 8 , do, C] 2 , C ⁇ 4 , C 16 , C ⁇ 8 , C 20 and C 22 fatty acids.
• Exemplary diglycerides include, in particular, diolein, dipalmitolein and mixed caprylin-caprin diglycerides.
• Preferred triglycerides include but are not limited to vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, medium and long-chain triglycerides, structured triglycerides and mixtures thereof.
• Preferred triglycerides include but are not limited to almond oil, babassu oil, borage oil, blackcurrant seed oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, evening primrose oil, grapeseed oil, groundnut oil, mustard seed oil, olive oil, palm oil, palm kernel oil, peanut oil, grapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated palm oil, hydrogenated soybean oil, hydrogenated vegetable oil, hydrogenated cottonseed and castor oil, partially hydrogenated soybean oil, partially hydrogenated soy and cottonseed oil, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyceryl triundecanoate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl trilinolenate,
• the preferred triglyceride can be a medium chain triglyceride commercially known as Labrafac CC ® .
• Other preferred triglycerides include, for example, neutral oils such as neutral plant oils, and in particular, fractionated coconut oils such as the commercially available MIGLYOL®, which includes but is not limited to MIGLYOL 810 ® ; MIGLYOL 812 ® ; MIGLYOL 818 ® ; and CAPTEX 355 ® .
• a preferred lipophilic phase component can be the product Miglyol 812 ® . See U.S. Patent No. 5,342,625.
• Suitable triglycerides include but are not limited to caprylic-capric acid triglycerides such as commercially known as MYRITOL ® , which includes but is not limited to MYRITOL 813 ® .
• Other suitable products of this class include but are not limited to CAPMUL MCT ® , CAPTEX 200 ® , CAPTEX 300 ® , CAPTEX 800 ® , NEOBEE MS ® and MAZOL 1400 ® .
• the emulsion pre-concentrates further comprise one or more surfactants.
• surfactants that can be used include but are not limited to hydrophilic or lipophilic surfactants, which include but are not limited to anionic, cationic, non-ionic and amphoteric surfactants or mixtures thereof.
• surfactants are non- ionic hydrophilic and non-ionic lipophilic surfactants.
• suitable hydrophilic surfactants include but are not limited to reaction products of natural or hydrogenated vegetable oils and ethylene glycol such as polyoxyethylene glycolated natural or hydrogenated vegetable or castor oils.
• the reaction products may be obtained by known methods which include but are not limited to the reaction of a natural or hydrogenated castor oil with ethylene oxide in a molar ratio of from about 1 :35 to about 1 :60.
• the free polyethylene glycol components can be removed from the product using the methods taught in German Auslegeschrifien 1,182,388 and 1,518,819.
• hydrophilic surfactants include but are not limited to polyoxyethylene- sorbitan-fatty acid esters, which include but are not limited to mono-and trilauryl, palmityl, stearyl and oleyl esters such as the following commercially known TWEEN ® products:
• TWEEN 20 (polyoxyethylene(20)sorbitanmonolaurate), TWEEN 40 ® (polyoxyethylene(20)sorbitanmonopalmitate), TWEEN 60 ® (polyoxyethylene(20)sorbitanmonostearate), TWEEN 80 ® (polyoxyethylene(20)sorbitanmonooleate), TWEEN 65 ® (polyoxyethylene(20)sorbitantristearate), TWEEN 85 ® (polyoxyethylene(20)sorbitantrioleate), TWEEN 21 ® (polyoxyethylene(4)sorbit--nmonolaurate), TWEEN 61 ® (polyoxyethylene(4)sorbitanmonostearate) and TWEEN 81 ® (polyoxyethylene(5)sorbitanmonooleate). [0178] The most preferred products of this class for use in the compositions are
• suitable hydrophilic surfactants include but are not limited to polyoxyethylene alkylethers, polyoxyethylene glycol fatty acid esters such as polyoxyethylene stearic acid esters, polyglycerol fatty acid esters, polyoxyethylene glycerides, polyoxyethylene vegetable oils and polyoxyethylene hydrogenated vegetable oils.
• hydrophilic surfactants include but are not limited to the products of reaction mixtures of polyols and one or more members of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols; polyoxyethylene-polyoxypropylene copolymers and block co-polymers; dioctylsuccinate, dioctylsodiumsulfosuccinate, di-[2-ethylhexyl]- succinate or sodium lauryl sulfate; phospholipids, and preferably lecithins such as soya bean lecithins; propylene glycol mono- and di- fatty acid esters such as, for example, propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate and propylene glycol stearate.
• the fatty acid ester can be propylene glycol caprylic- capric acid diester.
• suitable hydrophilic surfactants include but are not limited to bile salts such as sodium taurocholate.
• suitable lipophilic surfactants include but are not limited to alcohols, polyoxyethylene alkylethers, fatty acids, bile acids, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acids esters, polyethylene glycol fatty acids esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid esters of mono- or di-glycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sterols
• suitable lipophilic surfactants include but are not limited to trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols. Such trans-esterification products are known in the art and may be obtained using methods taught in U.S. Pat. No. 3,288,824. These trans- esterification products include but are not limited to reaction mixtures of one or more natural vegetable oils such as maize oil, kernel oil, almond oil, ground nut oil, olive oil, palm oil with one or more polyethylene glycols. The preferred polyethylene glycols have an average molecular weight of from 200 to 800.
• the products are obtained by trans-esterification of a 2:1 molar ratio of a natural vegetable oil triglyceride to polyethylene glycol.
• Various forms of trans- esterification products are commercially known as LABRAFIL ® .
• suitable lipophilic surfactants include but are not limited to oil-soluble vitamin derivatives such as tocopherol PEG- 1000 succinate ("vitamin E TPGS”), mono glycerides, diglycerides and mixtures thereof; esterification products of caprylic or capric acid with glycerol; sorbitan fatty acid esters; pentaerythritol and pentaerythrite fatty acid esters; and polyalkylene glycol ethers such as pentaerythrite-dioleate, -distearate, -monolaurate, -polyglycol ethers; monoglycerides such as glycerol monooleate, glycerol monopalmitate and glycerol monostearate; glycerol triacetate or (l,2,3)-triacetin; sterols and derivatives including but not limited to cholesterols and derivatives thereof, and in particular, phytosterols such as products comprising oil-soluble vitamin derivatives such
• the surfactants that are suitable for use in the present pharmaceutical formulations may include surfactants containing triglycerides.
• examples of commercial surfactant compositions containing triglycerides include but are not limited to GELUCIRE ® , MAISINE ® and IMWITOR ® .
• these compounds are the saturated polyglycolized glycerides such as GELUCIRE 44/14 ® , GELUCIRE 50/13 ® and GELUCIRE 53/10 ® ; semi- synthetic triglycerides such as GELUCIRE 33/01 ® , GELUCIRE 39/01 ® ; and other GELUCIRE ® surfactant compositions such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, etc.
• suitable commercial surfactant compositions include but are not limited to linoleic glycerides such as MAISINE 35-1 ® and caprylic/capric glycerides such as IMWITOR 742 ® . See U.S. Patent No. 6,267,985. Persons skilled in the art will recognize that there are other commercial surfactant compositions that have significant triglyceride contents, and will appreciate that compositions containing triglycerides as well as surfactants may be suitable to provide all or part of the lipophilic phase components, as well as all or part of the surfactants.
• the emulsion pre-concentrates of the present invention may optionally comprise one or more hydrophilic phase components.
• Suitable hydrophilic phase components include but are not limited to ethers of alkanediols and preferably diethers.
• the one or more hydrophilic phase components may comprise, for example, a pharmaceutically acceptable C ⁇ -C 5 alkyl or tetrahydrofurfuryl ether of a low molecular weight mono- or poly- oxy- alkanediol.
• the alkanediol can be a C 2 -C ⁇ 2 oxy-alkanediol and preferably a C 4 oxy- alkanediol.
• the oxy-alkanediol can be straight-chained.
• exemplary hydrophilic phase components for use in relation to the present invention are commercially known as TRANSCUTOL ® and COLYCOFUROL®. See U.S. Patent No. 5,342,625.
• the hydrophilic phase component may include one or more additional ingredients.
• additional ingredients comprise materials in which the vitamin D compound can be sufficiently soluble, such that the performance of the hydrophilic phase component as a carrier of the vitamin D compound is not materially impaired.
• Other possible hydrophilic phase components include but are not limited to lower alkanols such as C ⁇ -C 5 alkanols and preferably ethanol.
• the hydrophilic phase component comprises 1,2-propyleneglycol.
• any pharmaceutical formulations ofthe invention may further comprise one or more additives.
• Additives that are well-known in the art include but are not limited to detackifiers, anti-foaming agents, buffering agents, antioxidants such as ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols such as ⁇ -tocopherol (vitamin E), preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants and mixtures thereof. Persons of skill in the art can readily determine the amounts of such additives required to achieve the desired properties.
• the additives may also comprise thickening agents and salts thereof.
• Thickening agents may be included for a variety of reasons including but not limited to providing a sustained release effect. However, where oral administration is intended, thickening agents will generally not be required and are generally less preferred. Thickening agents are generally indicated for topical application. Suitable thickening agents known in the art include but are not limited to pharmaceutically acceptable polymeric materials and inorganics. In a preferred embodiment, thickening agents include but are not limited to polyacrylate and polyacrylate co-polymer resins, poly-acrylic acid and poly- acrylic acid/methacrylic acid resins, celluloses and cellulose derivatives.
• cellulose derivatives include but are not limited to acylated celluloses such as cellulose- acetates, cellulose-acetatephthalates, cellulose- acetatesuccinates and hydroxypropylmethyl cellulose phthalates. Salts of cellulose and cellulose derivatives include but are not limited to sodiumcarboxymethyl cellulose.
• Preferred cellulose derivatives include but are not limited to alkyl celluloses such as methyl, ethyl and propyl celluloses; hydroxyalkyl celluloses such as hydroxypropyl celluloses and hydroxypropylalkyl celluloses.
• the hydroxypropylalkyl celluloses include but are not limited to hydroxypropylmethyl celluloses.
• other additives can serve as thickening agents and include but are not limited to polyvinylpyrrolidones such as poly-N- vinylpyrrolidones and vinylpyrrolidone co-polymers.
• Vinylpyrrolidone copolymers include but are not limited to vinylpyrrolidone-vinylacetate copolymers, polyvinyl resins such as polyvinylacetates and polyvinylalcohols and polymeric materials.
• the polymeric additives include but are not limited to gum traganth, gum arabicum, alginates such as alginic acid and salts of alginic acid such as the sodium alginates.
• inorganic thickening agents are suitable and include but are not limited to atapulgite, bentonite and silicates.
• the silicates include but are not limited to hydrophilic silicon dioxide products such as alkylated silica gels and are preferably methylated.
• the inorganic thickening agents are colloidal silicon dioxide products.
• the lipophilic phase components can suitably be present in an amount of from about 30% to about 90% by weight based upon the total weight of the composition. In a preferred embodiment, the lipophilic phase component can be present in an amount of from about 50% to about 85% by weight based upon the total weight ofthe composition.
• the one or more surfactants can suitably be present in an amount of from about 1% to about 50% by weight based upon the total weight of the composition. In a preferred embodiment, the one ore more surfactants can be present in an amount of from about 5% to about 40% by weight based upon the total weight ofthe composition. More preferably, the one or more surfactants can be present in an amount of from about 10% to about 30% by weight based upon the total weight ofthe composition.
• the amount of vitamin D compound in compositions may vary according to a variety of factors. Examples of factors that can vary the amount of vitamin D compound include but are not limited to the intended route of administration and the extent to which other components are present.
• the vitamin D compound can be present in an amount of from about 0.005% to 20% by weight based upon the total weight ofthe composition. In other embodiments, the vitamin D compound can be present in an amount of from about 0.01% to 15% by weight based upon the total weight of the composition. In a preferred embodiment, the vitamin D compound can be present in an amount of from about 0.1% to about 10% by weight based upon the total weight ofthe composition.
• the hydrophilic phase component can be present in an amount of from about 2% to about 20% by weight based upon the total weight of the composition. In other embodiments, the hydrophilic phase component can be present in an amount of from about 5% to 15% by weight based upon the total weight of the composition. In a preferred embodiment, the hydrophilic phase component can be present in an amount of from about 8% to 12% by weight based upon the total weight ofthe composition.
• the emulsion pre-concentrate may be semisolid.
• Semisolid formulations may comprise, for example, one or more lipophilic phase components present in an amount of from about 60% to about 80% by weight based upon the total weight ofthe composition, one or more surfactants present in an amount of from about 5% to about 35% by weight based upon the total weight of the composition and one or more vitamin D compounds present in an amount of from about 0.01% to about 15% by weight based upon the total weight of the composition.
• the emulsion pre-concentrate may be liquid.
• Liquid formulations may comprise, for example, one or more lipophilic phase components present in an amount of from about 50% to about 60% by weight based upon the total weight ofthe composition, one or more surfactants present in an amount of from about 4% to about 25% by weight based upon the total weight of the composition, one or more vitamin D compounds present in an amount of from about 0.01% to about 15% by weight based upon the total weight of the composition and one or more hydrophilic phase components present in an amount of from about 5% to about 10% by weight based upon the total weight of the composition. Additional compositions that may be used include the following, wherein the percentage of each component is by weight based upon the total weight of the composition excluding the active vitamin D compound:
• Vitamin E TPGS about 30% Miglyol 812 about 50%;
• Vitamin E TPGS about 50% Miglyol 812 about 50%;
• Vitamin E TPGS about 20% Miglyol 812 about 30%;
• PEG 4000 about 50%
• Vitamin E TPGS about 50% PEG 4000 about 50%;
• Vitamin E TPGS about 33.3% PEG 4000 about 33.3%;
• Vitamin E TPGS about 50%
• Vitamin E TPGS about 50%
• Vitamin E TPGS about 5%
• Vitamin E TPGS about 5%
• Miglyol 812 about 65%
• PEG 4000 about 30%
• Vitamin E TPGS about 10% Miglyol 812 about 90%;
• Vitamin E TPGS about 5% Miglyol 812 about 85% PEG 4000 about 10%;
• Vitamin E TPGS about 10% Miglyol 812 about 80%
• PEG 4000 about 10%.
• parenteral dosage forms can be administered parenterally.
• Parenteral dosage forms can be administered by various routes including but not limited to intravenous, including but not limited to bolus and drip injections, intramuscular and intraarterial.
• the parenteral dosage forms are sterile or capable of being sterilized prior to administration to a subject since they typically bypass the subject's natural defenses against contaminants.
• parenteral dosage forms include but are not limited to solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection and emulsions.
• the formulations useful in the present invention include but are not limited to CALCUEX ® , which is an example of a currently available intravenous vitamin D compound formulation which can contain 1 ⁇ g calcitriol, 4 mg of Polysorbate 20, 2.5 mg of sodium ascorbate and optionally either HCI or NaOH for pH adjustment.
• Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well-known to those skilled in the art.
• suitable vehicles for parenteral dosage forms include but are not limited to Water for Injection USP; aqueous vehicles including but not limited to Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection and Lactated Ringer's Injection; water- miscible vehicles including but not limited to ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.
• compounds that increase the solubility of the pharmaceutical agents can be inco ⁇ orated into the parenteral dosage forms.
• cyclodextrin and its derivatives can be used to increase the solubility of a thalidomide analogue and its derivatives. See, e.g., U.S. Patent No. 5,134,127, which is inco ⁇ orated herein by reference.
• the present invention also encompasses a finished packaged and labeled pharmaceutical product.
• This article of manufacture includes the appropriate unit dosage form in an appropriate vessel or container such as a glass vial or other container that is hermetically sealed.
• the active ingredient e.g. one or more vitamin D compounds which are preferably active and more preferably calcitriol
• the unit dosage form may be a solid suitable for oral delivery.
• the unit dosage form is suitable for intravenous delivery.
• the invention also encompasses solutions, which are preferably sterile, suitable for intravenous delivery.
• the dosage form is a solution suitable for intravenous administration, comprising at least one unit dosage form of one or more vitamin D compounds, such as, e.g., CALCUEX ® .
• the unit dosage form is an oral emulsion pre- concentrate and comprises about 15 ⁇ g of calcitriol in addition to the following excipients with the amount given in approximate percentage by weight: 65% MIGLYOL 812N ® , 30% GELUCIRE 44/14 ® , 5% vitamin-E 7PGS and about 0.05%) each of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
• BHT butylated hydroxytoluene
• BHA butylated hydroxyanisole
• the packaging material and container are designed to protect the stability of the product during storage and shipment.
• the packaging material and container can be designed to protect the product from light and from high temperatures in order to protect the stability of the product.
• the products of the invention include instructions for use or other informational material that advise the physician, technician or patient on how to appropriately treat the disease or disorder in question.
• the article of manufacture includes instruction means indicating or suggesting a dosing regimen including but not limited to actual doses and monitoring procedures.
• the invention provides an article of manufacture comprising packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within said packaging material, wherein said pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and said packaging material includes instruction means which indicate that said vitamin D compound can be used to treat MDS, or ameliorate a symptom thereof, by administering the specific doses and using the specific dosing regimens described herein.
• packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like
• said packaging material includes instruction means which indicate that said vitamin D compound can be used to treat MDS, or ameliorate a symptom thereof, by administering the specific doses and using the specific dosing regimens described herein.
• the invention provides an article of manufacture comprising packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within said packaging material, wherein said pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and wherein said packaging material includes instruction means which indicate that said vitamin D compound can be used to treat MDS by administering specific doses and using specific dosing regimens as described herein.
• packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like
• said pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol
• said packaging material includes instruction means which indicate that said vitamin D compound can be used to treat MDS by administering specific doses and using specific dosing regimens as described herein.
• the invention provides an article of manufacture comprising packaging material, such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of each pharmaceutical agent contained within said packaging material, wherein one pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and the other pharmaceutical agent comprises a therapeutic agent other than a vitamin D compound, and wherein said packaging material includes instruction means which indicate that said agents can be used to treat the symptoms of MDS by administering the specific doses and using the specific dosing regimens as described herein.
• packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like
• i.v. intravenous
• the invention provides an article of manufacture comprising packaging material, such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of each pharmaceutical agent contained within said packaging material, wherein one pharmaceutical agent comprises one or more vitamin D compounds and the other pharmaceutical agent comprises a therapeutic agent other than a vitamin D compound, and wherein said packaging material includes instruction means which indicate that said agents can be used to treat MDS by administering specific doses and using specific dosing regimens as described herein.
• packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like
• i.v. intravenous
• the invention provides an article of manufacture comprising packaging material, such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of each pharmaceutical agent contained within said packaging material, wherein one pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and the other pharmaceutical agent comprises one or more hematopoietic growth factors or cytokines, which are preferably r- HuEPO, r- metHuG-CSF or any combination thereof, and wherein said packaging material includes instruction means which indicate that said agents can be used to treat the symptoms of MDS by administering specific doses and using specific dosing regimens as described herein.
• packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like
• at least one unit dosage form of each pharmaceutical agent contained within said packaging material wherein one pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calc
• the invention provides an article of manufacture comprising packaging material, such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of each pharmaceutical agent contained within said packaging material, wherein one pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and the other pharmaceutical agent comprises one or more hematopoietic growth factors or cytokines, which are preferably r-HuEPO, r-metHuG-CSF or any combination thereof, and wherein said packaging material includes instruction means which indicate that said agents can be used to treat MDS by administering specific doses and using specific dosing regimens as described herein.
• packaging material such as a box, bottle, tube, vial, container, intravenous (i.v.) bag, envelope and the like
• i.v. intravenous
• the instruction means enclosed in an article of manufacture indicates or suggests that the plasma concentration of calcium be monitored one or more times before and/or after a dose.
• the instruction means enclosed in an article of manufacture can indicate that the blood calcium concentration be taken before the first dose and after one or more subsequent doses.
• the instruction means enclosed in an article of manufacture indicates that the vitamin D compounds are used to treat MDS in a subject, and that the blood calcium concentration in said subject is less than about 10.5 mg/dL.
• the instruction means enclosed in an article of manufacture indicates that the vitamin D compounds are used to treat the anemia of MDS, and that the blood calcium concentration in said subject is less than about 10.5 mg/dL.
• the informational material enclosed in an article of manufacture for use in treating MDS, or ameliorating one or more symptoms thereof also indicates that subjects with hypercalcemia are not administered a pharmaceutical composition comprising a vitamin D compound.
• the informational material enclosed in an article of manufacture for use in treating MDS, or ameliorating one or more symptoms thereof also indicates that subjects with grade 2, grade 3 or grade 4 of hypercalcemia are not administered a pharmaceutical composition comprising a vitamin D compound.
• the preferred oral dosage form (“the preferred formulation”) comprises about 15 ⁇ g of calcitriol in addition to the following excipients with the amount given in approximate percentage by weight: 65% MIGLYOL 812N ® , 30% GELUCIRE 44/14 ® , 5% vitamin-E TPGS and about 0.05% each of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
• BHT butylated hydroxytoluene
• BHA butylated hydroxyanisole
• the pharmacokinetic parameters calculated were maximal concentration in plasma ("C MAX "), time at maximal concentration (“-MAX”) > half-life ("t ⁇ / 2 "), and trapezoidal area determined from the concentration vs. time data from time 0 to 24 hours (“AUC 0 . 2 "), from time 0-72 hours (“AUC 0 - 72 ”) and from time 0 to infinity (“AUC0-”).
• the pharmacokinetic data show that the preferred formulation responds linearly and predictably to increasing dosages and there was no evidence of saturation of abso ⁇ tion. Further, the pharmacokinetic data show that the administered doses of calcitriol achieve higher peak plasma concentrations than previously had been believed to be possible without inducing hypercalcemia.
• the methods of the invention provide a safe and effective method for achieving high peak plasma concentrations of vitamin D compounds to treat MDS, or ameliorate a symptom thereof, without causing hypercalcemia.
• EXAMPLE 2 VITAMIN D MONOTHERAPY
• the following treatment program provides an example of use of the above-described methods to treat MDS, or ameliorate a symptom thereof.
• Monitoring of the subjects comprises physical examination, ECOG performance status, hematology, anemia work-up, hematology, blood chemistry, urinalysis, study drug administration, transfusion record, adverse events, concomitant medications, FACT-An questionnaire, bone marrow aspirate and biopsy, peripheral blood smear, endogenous EPO, and iron status.
• the following treatment program provides another example of use of the above- described methods to treat MDS, or ameliorate a symptom thereof.
• Monitoring of the subjects comprises physical examination, ECOG performance status, hematology, anemia work-up, hematology, blood chemistry, urinalysis, study drug administration, transfusion record, adverse events, concomitant medications, FACT-An questionnaire, bone marrow aspirate and biopsy, peripheral blood smear, endogenous EPO, and iron status.
• the subjects are further monitored to determine whether they are erythroid responders or non-responders to the vitamin D compound administration.
• a major erythroid responder is a subject with a baseline hemoglobin of less than 11 g/dL who experiences an increase of greater than or equal to 2 g/dL from the baseline.
• a minor erythroid responder is a subject with a baseline hemoglobin of less than 11 g/dL who experiences an increase of 1 to 2 g/dL from baseline. Responders continue to receive calcitriol at the same dose and frequency, while non-responders begin taking EPO in combination with the vitamin D compounds.
• the starting dose of EPO is 10,000 U once per day. If there is no improvement after six weeks, the dose of EPO is increased to 20,000 U once per day. EPO is administered subcutaneously, and the subject's iron status is also monitored.
• Patient #1 exhibited a rise in hemoglobin of more than one gram per deciliter as compared to baseline, constituting a protocol defined "minor response" (Fig. 2A).
• Patient #2 demonstrated a 50% decrease in required red blood cell transfusions as compared to baseline (Fig. 2B).
• Patient #3 exhibited a rise in hemoglobin of more than two grams per deciliter as compared to baseline, constituting a protocol defined "major response" (Fig. 2C).
• the results from all three patients are indicative of a beneficial effect of high dose pulse administration of calcitriol for the treatment of MDS.

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