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`WO 2009/139888
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`PCT/0S2009/002999
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`1
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`ORAL FORMULATIONS OF CYTIDINE ANALOGS
`AND METHODS OF USE THEREOF
`
`I.
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`(0001]
`
`This application claims priority to U.S. Provisional Patent Application Nos.
`
`61/053,609, filed May 15, 2008; 61/201,145, filed December 5, 2008; and 61/157,875, filed
`
`March 5, 2009, the contents of each of which are incorporated by reference herein in their
`
`entireties.
`
`II.
`
`FIELD
`
`(0002]
`
`Provided herein are pharmaceutical formulations comprising cytidine analogs, or
`
`their salts, solvates, hydrates, precursors, and/or derivatives thereof, for oral administration in
`
`subjects. Also provided are methods for making the formulations and methods for using the
`
`formulations to treat diseases and disorders including cancer, disorders related to abnormal
`
`cell proliferation, hematologic disorders, and immune disorders, among others.
`
`III.
`
`BACKGROUND
`
`(0003]
`
`Cancer is a major worldwide public health problem; in the United States alone,
`
`approximately 570,000 cancer-related deaths were expected in 2005. See, e.g., Jemal et al.,
`
`CA Cancer J Clin. 55(1):10-30 (2005). Many types of cancer have been described in the
`
`medical literature. Examples include cancer of the blood, bone, lung (e.g., non-small-cell
`
`lung cancer and small-cell lung cancer), colon, breast, prostate, ovary, brain, and intestine.
`
`The incidence of cancer continues to climb as the general population ages and as new forms
`
`of cancer develop. A continuing need exists for effective therapies to treat subjects with
`
`cancer.
`
`(0004] Myelodysplastic syndromes (MDS) refers to a diverse group of hematopoietic
`
`stem cell disorders. MDS affects approximately 40,000-50,000 people in the U.S. and
`
`75,000-85,000 subjects in Europe. MDS may be characterized by a cellular marrow with
`
`impaired morphology and maturation (dysmyelopoiesis), peripheral blood cytopenias, and a
`
`variable risk of progression to acute leukemia, resulting from ineffective blood cell
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`production. See, e.g., The Merck Manual 953 (17th ed. 1999); List et al., J Clin. Oneal.
`
`8:1424 (1990).
`
`[0005) MDS are grouped together because of the presence of dysplastic changes in one or
`
`more of the hematopoietic lineages including dysplastic changes in the myeloid, erythroid,
`
`and megakaryocytic series. These changes result in cytopenias in one or more of the three
`
`lineages. Patients afflicted with MDS may develop complications related to anemia,
`
`neutropenia (infections), and/or thrombocytopenia (bleeding). From about 10% to about 70%
`
`of patients with MDS may develop acute leukemia. In the early stages of MDS, the main
`
`cause of cytopenias is increased programmed cell death (apoptosis). As the disease
`
`progresses and converts into leukemia, a proliferation of leukemic cells overwhelms the
`
`healthy marrow. The disease course differs, with some cases behaving as an indolent disease
`
`and others behaving aggressively with a very short clinical course that converts into an acute
`
`form of leukemia. The majority of people with higher risk MDS eventually experience bone
`
`marrow failure. Up to 50% ofMDS patients succumb to complications, such as infection or
`
`bleeding, before progressing to AML.
`
`[0006)
`
`Primary and secondary MDS are defined by taking into account patients' prior
`
`history: previous treatments with chemotherapy, radiotherapy or professional exposure to
`
`toxic substances are factors delineating secondary MDS (sMDS) from primary MDS.
`
`Cytogenetically, one difference between the two groups is the complexity of abnormal
`
`karyotypes; single chromosome aberrations are typical for primary MDS, while multiple
`
`changes are more frequently seen in secondary disorders. Some drugs may have specific
`
`targets such as hydroxurea for 17p and topoisomerases inhibitors for 1 lq23 and 21q22. The
`
`genetic changes in the malignant cells of MDS result mainly in the loss of genetic material,
`
`including probable tumor suppressor genes.
`
`[0007)
`
`An international group of hematologists, the French-American-British (FAB)
`
`Cooperative Group, classified MDS into five subgroups, differentiating them from acute
`
`myeloid leukemia. See, e.g., The Merck Manual 954 (17th ed. 1999); Bennett J. M., et al.,
`
`Ann. Intern. Med., I 03( 4): 620-5 (1985); and Besa E. C., Med. Clin. North Am. 76(3): 599-
`
`617 ( 1992). An underlying trilineage dysplastic change in the bone marrow cells of the
`
`patients is found in all subtypes. Information is available regarding the pathobiology of
`
`MDS, certain MDS classification systems, and particular methods of treating and managing
`
`MDS. See, e.g., U.S. Patent No. 7,189,740 (issued March 13, 2007), which is incorporated by
`
`reference herein in its entirety.
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`Nucleoside analogs have been used clinically for the treatment of viral infections
`
`[0008]
`and cancer. Most nucleoside analogs are classified as anti-metabolites. After they enter the
`
`cell, nucleoside analogs are successively phosphorylated to nucleoside 5'-mono-phosphates,
`
`di-phosphates, and tri-phosphates.
`
`[0009]
`
`5-Azacytidine (National Service Center designation NSC-102816; CAS Registry
`
`Number 320-67-2), also known as azacitidine, AZA, or 4-amino-l-~-D-ribofuranosyl-1,3,5-
`
`triazin-2(1H)-one, is currently marketed as the drug product VIDAZA ®. 5-Azacytidine is a
`
`nucleoside analog, more specifically a cytidine analog. 5-Azacytidine is an antagonist of its
`
`related natural nucleoside, cytidine. 5-Azacytidine and 5-aza-2'-deoxycytidine (also known
`
`as decitabine, an analog of deoxycytidine) are also antagonists of deoxycytidine. A structural
`
`difference between these cytidine analogs and their related natural nucleoside is the presence
`
`of a nitrogen at position 5 of the cytosine ring in place of a carbon. 5-Azacytidine may be
`
`defined as having the molecular formula CsH12N4Os, a molecular weight of 244.21 grams per
`
`mole, and the following structure:
`
`NH2
`
`N~N
`
`llN~O
`HO'l..-~oJ
`tf-il
`
`OH OH
`
`5-Azacytidine.
`
`[0010]
`
`Other members of the class of cytidine analogs include, for example: 1-~-D-
`
`arabinofuranosylcytosine (Cytarabine or ara-C); 5-aza-2'-deoxycytidine (Decitabine or 5-aza(cid:173)
`
`CdR); pseudoisocytidine (psi ICR); 5-fluoro-2'-deoxycytidine (FCdR); 2'-deoxy-2',2'(cid:173)
`
`difluorocytidine (Gemcitabine); 5-aza-2'-deoxy-2',2'-difluorocytidine; 5-aza-2'-deoxy-2'(cid:173)
`
`fluorocytidine; l-~-D-ribofuranosyl-2(1H)-pyrimidinone (Zebularine); 2',3'-dideoxy-5-fluoro-
`
`3'-thiacytidine (Emtriva); 2'-cyclocytidine (Ancitabine); l-~-D-arabinofuranosyl-5-
`
`azacytosine (Fazarabine or ara-AC); 6-azacytidine (6-aza-CR); 5,6-dihydro-5-azacytidine
`(dH-aza-CR); N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (Capecitabine); N4-octadecyl(cid:173)
`cytarabine; and elaidic acid cytarabine.
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`[0011]
`
`After its incorporation into replicating DNA, 5-azacytidine or 5-aza-2'-
`
`deoxycytidine forms a covalent complex with DNA methyltransferases. DNA
`
`methyltransferases are responsible for de novo DNA methylation and for reproducing
`
`established methylation patterns in daughter DNA strands ofreplicating DNA. Inhibition of
`
`DNA methyltransferases by 5-azacytidine or 5-aza-2'-deoxycytidine leads to DNA
`
`hypomethylation, thereby restoring normal functions to morphologically dysplastic, immature
`
`hematopoietic cells and cancer cells by re-expression of genes involved in normal cell cycle
`
`regulation, differentiation and death. The cytotoxic effects of these cytidine analogs cause
`
`the death of rapidly dividing cells, including cancer cells, that are no longer responsive to
`
`normal cell growth control mechanisms. 5-azacytidine, unlike 5-aza-2'-deoxycytidine, also
`
`incorporates into RNA. The cytotoxic effects of azacitidine may result from multiple
`
`mechanisms, including inhibition of DNA, RNAand protein synthesis, incorporation into
`
`RNA and DNA, and activation of DNA damage pathways.
`
`[0012]
`
`5-Azacytidine and 5-aza-2'-deoxycytidine have been tested in clinical trials and
`
`showed significant anti-tumor activity, such as, for example, in the treatment of
`
`myelodysplastic syndromes (MDS), acute myelogenous leukemia (AML), chronic
`
`myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), and non Hodgkin's
`
`lymphoma (NHL). See, e.g., Aparicio et al., Curr. Opin. Invest. Drugs 3(4): 627-33 (2002).
`
`5-Azacytidine has undergone NCI-sponsored trials for the treatment of MDS and has been
`approved for treating all F AB subtypes of MDS. See, e.g., Komblith et al., J. Clin. Oncol.
`
`20(10): 2441-2452 (2002); Silverman et al., J. Clin. Oncol. 20(10): 2429-2440 (2002). 5-
`
`Azacytidine may alter the natural course of MDS by diminishing the transformation to AML
`
`through its cytotoxic activity and its inhibition of DNA methyltransferase. In a Phase III
`
`study, 5-azacytidine administered subcutaneously significantly prolonged survival and time
`
`to AML transformation or death in subjects with higher-risk MDS. See, e.g., P. Fenaux et al.,
`
`Lancet Oncol., 2009, 10(3):223-32; Silverman et al., Blood 106(11): Abstract 2526 (2005).
`
`[0013]
`
`5-Azacytidine and other cytidine analogs are approved for subcutaneous (SC) or
`
`intravenous (IV) administration to treat various proliferative disorders. Oral dosing of
`
`cytidine analogs would be more desirable and convenient for patients and doctors, e.g., by
`
`eliminating injection-site reactions that may occur with SC administration and/or by
`
`permitting improved patient compliance. However, oral delivery of cytidine analogs has
`
`proven difficult due to combinations of chemical instability, enzymatic instability, and/or
`
`poor permeability. For example, cytidine analogs have been considered acid labile and
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`unstable in the acidic gastric environment. Previous attempts to develop oral dosage forms of
`
`cytidine analogs have required enteric coating of the drug core to protect the active
`
`pharmaceutical ingredient (API) from what was understood and accepted to be
`
`therapeutically unacceptable hydrolysis in the stomach, such that the drug is preferably
`
`absorbed in specific regions of the lower gastrointestinal tract, such as the jejunum in the
`
`small intestine. See, e.g., Sands, et al., U.S. Patent Publication No. 2004/0162263 (App. No.
`
`10/698,983). In addition, a generally accepted belief in the art has been that water leads to
`
`detrimental hydrolytic degradation of cytidine analogs during formulation, subsequently
`
`affecting the stability of the API in the dosage form. As a result, coatings applied to the drug
`
`core for prospective oral delivery of cytidine analogs have previously been limited to organic
`
`solvent-based systems to minimize exposure of the API to water.
`
`[0014)
`
`A great need remains for oral formulations and dosage forms of cytidine analogs,
`
`such as, e.g., 5-azacytidine, to potentially permit, inter alia, more advantageous dosing
`
`amounts or dosing periods; improved pharmacokinetic profiles, pharmacodynamic profiles,
`
`or safety profiles; evaluation of the benefits oflong-term or maintenance therapies;
`
`development of improved treatment regimens that maximize biologic activity; use of cytidine
`
`analogs for treating new diseases or disorders; and/or other potential advantageous benefits.
`
`IV.
`
`SUMMARY
`
`[0015)
`
`Provided herein are pharmaceutical compositions comprising cytidine analogs,
`
`wherein the compositions release the API substantially in the stomach upon oral
`
`administration. Also provided are methods for making the compositions, and methods for
`
`using the compositions to treat diseases and disorders including cancer, disorders related to
`
`abnormal cell proliferation, and hematologic disorders, among others.
`
`[0016)
`
`In certain embodiments, the cytidine analog is 5-azacytidine. In other
`
`embodiments, the cytidine analog is 5-aza-2'-deoxycytidine (decitabine or 5-aza-CdR). In yet
`
`other embodiments, the cytidine analog is, for example: 1-P-D-arabinofuranosylcytosine
`
`(Cytarabine or ara-C); pseudoisocytidine (psi ICR); 5-fluoro-2'-deoxycytidine (FCdR); 2'(cid:173)
`
`deoxy-2',2'-difluorocytidine (Gemcitabine ); 5-aza-2'-deoxy-2' ,2'-difluorocytidine; 5-aza-2'(cid:173)
`
`deoxy-2'-fluorocytidine; l-P-D-ribofuranosyl-2(1H)-pyrimidinone (Zebularine); 2',3'-dideoxy-
`
`5-fluoro-3'-thiacytidine (Emtriva); 2'-cyclocytidine (Ancitabine); l-P-D-arabinofuranosyl-5-
`
`azacytosine (Fazarabine or ara-AC); 6-azacytidine (6-aza-CR); 5,6-dihydro-5-azacytidine
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`(dH-aza-CR); N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (Capecitabine); N4-octadecyl(cid:173)
`cytarabine; elaidic acid cytarabine; or their derivatives or related analogs.
`
`[0017]
`
`Certain embodiments herein provide compositions that are single unit dosage
`
`forms comprising a cytidine analog. Certain embodiments herein provide compositions that
`
`are non-enteric-coated. Certain embodiments herein provide compositions that are tablets
`
`comprising a cytidine analog. Certain embodiments herein provide compositions that are
`
`capsules comprising a cytidine analog. The capsules may be, e.g., a hard gelatin capsule or a
`
`soft gelatin capsule; particular embodiments provide hydroxypropyl methylcellulose (HPMC)
`
`capsules. In certain embodiments, the single unit dosage forms optionally further contain one
`
`or more excipients. In certain embodiments, the tablets optionally further contain one or
`
`more excipients. In other embodiments, the capsules optionally further contain one or more
`
`excipients. In certain embodiments, the composition is a tablet that effects an immediate
`
`release of the API upon oral administration. In other embodiments, the composition is a
`
`tablet that effects a controlled release of the API substantially in the stomach. In certain
`
`embodiments, the composition is a capsule that effects an immediate release of the API upon
`
`oral administration. In other embodiments, the composition is a capsule that effects a
`
`controlled release of the API substantially in the stomach. In particular embodiments, the
`
`tablet contains a drug core that comprises a cytidine analog, and optionally further contains a
`
`coating of the drug core, wherein the coating is applied to the drug core using an aqueous
`
`solvent, such as, for example, water, or non-aqueous solvent, such as, for example ethanol.
`
`[0018]
`
`Certain embodiments herein provide methods of making formulations of cytidine
`
`analogs intended for oral delivery. Further provided are articles of manufacture containing
`
`packaging material, an oral formulation of a cytidine analog, and a label that indicates that
`
`the formulation is for the treatment of certain diseases or disorders including, e.g., a cancer, a
`
`disorder related to abnormal cell proliferation, a hematologic disorder, or an immune
`
`disorder.
`
`[0019]
`
`Certain embodiments herein provide methods of using the formulations provided
`
`herein to treat diseases or disorders including, e.g., cancer, disorders related to abnormal cell
`
`proliferation, hematologic disorders, or immune disorders, among others. In certain
`
`embodiments, the formulations of cytidine analogs are orally administered to subjects in need
`
`thereof to treat a cancer or a hematological disorder, such as, for example, MDS, AML, ALL,
`
`CML, NHL, leukemia, or lymphoma; or a solid tumor, such as, for example, sarcoma,
`
`melanoma, carcinoma, or cancer of the colon, breast, ovary, gastrointestinal system, kidney,
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`lung (e.g., non-small-cell lung cancer and small-cell lung cancer), testicle, prostate, pancreas
`
`or bone. In certain embodiments, the formulations of cytidine analogs are orally
`
`administered to subjects in need thereof to treat an immune disorder. In certain
`
`embodiments, the oral formulations provided herein are co-administered with one or more
`
`therapeutic agents to provide a synergistic therapeutic effect in subjects in need thereof. In
`
`certain embodiments, the oral formulations provided herein are co-administered with one or
`
`more therapeutic agents to provide a resensitization effect in subjects in need thereof. The
`
`co-administered agents may be a cancer therapeutic agent, as described herein. In certain
`
`embodiments, the co-administered agent(s) may be dosed, e.g., orally or by injection.
`
`[0020]
`
`In particular embodiments, provided herein are tablets containing 5-azacytidine
`
`and methods for making and using the tablets to treat cancer, disorders related to abnormal
`
`cell proliferation, or hematologic disorders. In certain embodiments, the tablets optionally
`
`further contain one or more excipients such as, for example, glidants, diluents, lubricants,
`
`colorants, disintegrants, granulating agents, binding agents, polymers, and/or coating agents.
`
`Examples of ingredients useful in preparing certain formulations provided herein are
`
`described in, e.g., Etter et al., U.S. Patent Application Publication No. 2008/0057086 (App.
`
`No. 11/849,958), which is incorporated herein by reference in its entirety.
`
`[0021]
`
`Specific embodiments herein provide, inter alia, pharmaceutical compositions
`
`comprising a therapeutically effective amount of 5-azacytidine, wherein the composition
`
`releases the 5-azacytidine substantially in the stomach following oral administration to a
`
`subject. Further embodiments provide the aforementioned compositions, which: are
`
`immediate release compositions; do not have an enteric coating (i.e., are non-enteric-coated);
`
`are tablets; are capsules; further comprise an excipient selected from any excipient disclosed
`
`herein; further comprise a permeation enhancer; further comprise d-alpha-tocopheryl
`
`polyethylene glycol 1000 succinate; further comprise a permeation enhancer in the
`
`formulation at about 2% by weight relative to the total weight of the formulation; are
`
`essentially free of a cytidine deaminase inhibitor; are essentially free of tetrahydrouridine;
`
`have an amount of 5-azacytidine of at least about 40 mg; have an amount of 5-azacytidine of
`
`at least about 400 mg; have an amount of 5-azacytidine of at least about 1000 mg; achieve an
`
`area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to a
`
`subject; achieve an area-under-the-curve value of at least about 400 ng-hr/mL following oral
`
`administration to a subject; achieve a maximum plasma concentration of at least about 100
`
`ng/mL following oral administration to a subject; achieve a maximum plasma concentration
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`of at least about 200 ng/mL following oral administration to a subject; achieve a time to
`
`maximum plasma concentration of less than about 90 minutes following oral administration
`
`to a subject; and/or achieve a time to maximum plasma concentration of less than about 60
`
`minutes following oral administration to a subject.
`
`[0022)
`
`Specific embodiments herein provide a pharmaceutical composition for oral
`
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves an area-under-the-curve value of
`
`at least about 200 ng-hr/mL following oral administration.
`
`[0023)
`
`Specific embodiments herein provide a pharmaceutical composition for oral
`
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves an area-under-the-curve value of
`
`at least about 400 ng-hr/mL following oral administration.
`
`[0024)
`
`Specific embodiments herein provide a pharmaceutical composition for oral
`
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves a maximum plasma concentration
`
`of at least about 100 ng/mL following oral administration.
`
`[0025)
`
`Specific embodiments herein provide a pharmaceutical composition for oral
`
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves a maximum plasma concentration
`
`of at least about 200 ng/mL following oral administration.
`
`[0026)
`
`Specific embodiments herein provide a pharmaceutical composition for oral
`
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves a time to maximum plasma
`
`concentration of, e.g., less than about 6 hr, less than about 5 hr, less than about 4 hr, less than
`
`about 3 hr, less than about 2.5 hr, less than about 2 hr, less than about 1.5 hr, less than about 1
`
`hr, less than about 45 min, or less than about 30 min following oral administration. In
`
`specific embodiments, the presence of food may affect (e.g., extend) the total exposure and/or
`
`time to maximum plasma concentration.
`
`[0027)
`
`Specific embodiments herein provide a pharmaceutical composition for oral
`
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves a time to maximum plasma
`
`concentration of less than about 60 minutes following oral administration.
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`[0028)
`
`Specific embodiments herein provide any of the aforementioned compositions, as
`
`single unit dosage forms, tablets, or capsules.
`
`[0029)
`
`Specific embodiments herein provide, inter alia, methods for treating a subject
`
`having a disease associated with abnormal cell proliferation, comprising orally administering
`
`to the subject a pharmaceutical composition comprising a therapeutically effective amount of
`
`5-azacytidine, wherein the composition releases the 5-azacytidine substantially in the
`
`stomach following oral administration to the subject. Further embodiments herein provide
`
`the aforementioned methods, in which: the disease is myelodysplastic syndrome; the disease
`
`is acute myelogenous leukemia; the method further comprises co-administering to the subject
`
`in need thereof an additional therapeutic agent selected from any additional therapeutic agent
`
`disclosed herein; the composition is an immediate release composition; the composition does
`
`not have an enteric coating; the composition further comprises a permeation enhancer; the
`
`composition further comprises the permeation enhancer d-alpha-tocopheryl polyethylene
`
`glycol 1000 succinate; the composition further comprises d-alpha-tocopheryl polyethylene
`
`glycol 1000 succinate in the formulation at about 2% by weight relative to the total weight of
`
`the formulation; the method further comprises not co-administering a cytidine deaminase
`
`inhibitor with the cytidine analog; the composition is a single unit dosage form; the
`
`composition is a tablet; the composition is a capsule; the composition further comprises an
`
`excipient selected from any excipient disclosed herein; the amount of 5-azacytidine is at least
`
`about 40 mg; the amount of 5-azacytidine is at least about 400 mg; the amount of 5-
`
`azacytidine is at least about 1000 mg; the method achieves an area-under-the-curve value of
`
`at least about 200 ng-hr/mL following oral administration to the subject; the method achieves
`
`an area-under-the-curve value of at least about 400 ng-hr/mL following oral administration to
`
`the subject; the method achieves a maximum plasma concentration of at least about 100
`
`ng/mL following oral administration to the subject; the method achieves a maximum plasma
`
`concentration of at least about 200 ng/mL following oral administration to the subject; the
`
`method achieves a time to maximum plasma concentration of less than about 90 minutes
`
`following oral administration to the subject; and/or the method achieves a time to maximum
`
`plasma concentration of less than about 60 minutes following oral administration to the
`
`subject
`
`[0030)
`
`Specific embodiments herein provide, inter alia, pharmaceutical compositions
`
`comprising a therapeutically effective amount of 5-azacytidine, wherein the compositions are
`
`for treating a disease or disorder associated with abnormal cell proliferation, wherein the
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`compositions are prepared for oral administration, and wherein the compositions are prepared
`
`for release of the 5-azacytidine substantially in the stomach. Further embodiments herein
`
`provide the aforementioned compositions, which: have an amount of 5-azacytidine of about
`
`40 mg, about 400 mg, or about 1000 mg; are prepared to achieve an area-under-the-curve
`
`value of at least about 200 ng-hr/mL or 400 ng-hr/mL following oral administration; are
`
`prepared to achieve a maximum plasma concentration of at least about 100 ng/mL or 200
`
`ng/mL following oral administration; are prepared to achieve a time to maximum plasma
`
`concentration of less than about 60 minutes or 90 minutes after being administered; are
`
`prepared in the form of an immediate release composition; are prepared for oral
`
`administration in combination with an additional therapeutic agent selected from any
`
`additional therapeutic agent disclosed herein; are for treating myelodysplastic syndrome or
`
`acute myelogenous leukemia; further comprise a permeation enhancer; which further
`
`comprise the permeation enhancer d-alpha-tocopheryl polyethylene glycol I 000 succinate;
`
`are single unit dosage forms; are tablets or capsules; and/or further comprise an excipient
`
`selected from any excipient disclosed herein.
`
`[0031]
`
`Specific embodiments herein provide, inter alia, uses of 5-azacytidine for the
`
`preparation of a pharmaceutical composition for treating a disease associated with abnormal
`
`cell proliferation, wherein the composition is prepared for oral administration, and wherein
`
`the composition is prepared for release of the 5-azacytidine substantially in the stomach.
`
`Further embodiments herein provide the aforementioned uses, in which: the disease is
`
`myelodysplastic syndrome or acute myelogenous leukemia; the amount of 5-azacytidine is
`
`selected from any amount disclosed herein; and/or the composition is prepared for immediate
`
`release. Further embodiments provide, inter alia, methods for treating a subject having a
`
`disease or disorder provided herein by administering a pharmaceutical compositions provided
`
`herein, wherein the treatment results in improved survival of the subject.
`
`V.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0032]
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`Figure 1 represents processes and steps that may be used to make particular tablets
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`comprising azacitidine for oral dosing; in specific embodiments, one or more steps may be
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`optionally omitted.
`Figure 2 represents human PK profiles following 75 mg/m2 SC dosing of
`[0033]
`azacitidine on Days 1 and 7 in a multiple dose escalation study (n = 18). The X-axis
`represents time; the Y-axis represents azacitidine plasma concentrations (mean± SD).
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`[0034]
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`11
`Figure 3 represents human PK profiles following SC (75 mg/m2
`300 mg, and 360 mg) dosing of azacitidine in a multiple dose escalation study. The
`
`) and PO (240 mg,
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`azacitidine plasma PK profiles are compared among various doses. The X-axis represents
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`time; the Y-axis represents azacitidine plasma concentrations (mean± SD).
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`[0035]
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`Figure 4 represents PD data from an individual patient (Subject 02008, 80 year old
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`male, RAEB-1) collected during a multiple dose escalation study. The patient was dosed
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`with azacitidine Formulation #3, 240 mg. Platelets (K/µL), Hgb (g/dL), ANC (K/µL), and
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`Relative BM Blast(%) are plotted versus sampling dates over the course of the study.
`
`[0036]
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`Figure 5 represents PD data from an individual patient (Subject 02007, 76 year old
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`male, CMML) collected during a multiple dose escalation study. The patient was dosed with
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`azacitidine Formulation #3, 240 mg. Platelets (K/µL), Hgb (g/dL), ANC (K/µL), and
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`Relative BM Blast(%) are plotted versus sampling dates over the course of the study.
`
`[0037]
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`Figure 6 represents PD data from an individual patient (Subject 02004, 61 year old
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`male, MDS, MDACC) collected during a multiple dose escalation study. The patient was
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`dosed with azacitidine Formulation 1, 120 mg. Platelets (K/µL), Hgb (g/dL), ANC (K/µL),
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`and Relative BM Blast(%) are plotted versus sampling dates over the course of the study.
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`[0038]
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`Figure 7 represents a study design of a Rapid Aza Clinical Evaluation (RACE)
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`study CLOOS. Doses given on various days within a treatment cycle are depicted. Dose may
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`be administered± 1 day, as long as there is at least 48 hours between doses.
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`[0039]
`Figure 8 represents azacitidine human PK profiles from an individual patient
`(Subject 106003, N = 1) following SC (124 mg, 75 mg/m2
`) and PO (180 mg, 360 mg, 1,200
`mg, Formulation 4) dosing of azacitidine from a RACE clinical study. AUC(0-t) values for
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`the SC and PO doses are depicted.
`
`[0040]
`Figure 9 represents azacitidine human PK profiles from an individual patient
`(Subject 106004, N = 1) following SC (120 mg, 75 mg/m2
`mg, Formulation 6) dosing of azacitidine from a RACE clinical study. AUC(0-oo) values for
`
`) and PO (180 mg, 360 mg, 1,200
`
`the SC and PO doses are depicted.
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`[0041]
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`Figure 10 represents human PK profiles (linear scale) following SC and oral
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`administration of azacitidine in clinical studies.
`[0042]
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`Figure 11 represents human PK profiles (semi-log scale) following SC and oral
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`administration of azacitidine in clinical studies.
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`[0043]
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`Figure 12 represents human AUC values following SC dosing of azacitidine and
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`oral dosing of azacitidine with Formulations #3, #4, and #6 at various dosage levels in
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`clinical studies (CLOOS and CLOOS).
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`12
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`[0044]
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`Figure 13 represents human Cmax values in patients following SC dosing of
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`azacitidine and oral dosing of azacitidine with Formulations #3, #4, and #6 at various dosage
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`levels in clinical studies.
`
`[0045)
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`Figure 14 represents relative oral bioavailability in humans following oral dosing
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`of azacitidine with Formulations #3, #4, and #6 at various dosage levels.
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`[0046)
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`Figure 15 represents percent exposure in humans relative to SC administration
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`following oral dosing of azacitidine with Formulations #3, #4, and #6 at various dosage
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`levels.
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`[0047)
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`Figure 16 represents profiles of human plasma concentration versus time (linear
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`scale) following oral dosing of azacitidine with Formulations #3 and #6 and 180 mg (n=6).
`
`[0048)
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`Figure 17 represents linear scale profiles of human plasma concentration (ng/ml)
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`versus time (hr) following oral dosing of azacitidine with Formulations #3 and #6 and 360
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`mg (n=6).
`
`[0049)
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`Figure 18 represents a plot of values for individual ("ind") and mean azacitidine
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`ACU(O-inf) (ng*hr/ml) versus azacitidine dose (mg), with calculated linear regression lines
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`for Formulations #3 and #6.
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`[0050)
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`Figure 19 represents a comparison of azacitidine relative oral bioavailability (%)
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`(mean± SD) versus azacitidine dose (mg) following dosing with Formulation #3 or #6.
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`[0051)
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`Figure 20 represents a comparison of azacitidine exposure as compared to SC
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`dose (mean± SD) versus azacitidine dose (mg) following oral administration of Formulation
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`#3 or #6.
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`VI.
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`DETAILED DESCRIPTION
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`[0052)
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`Unless defined otherwise, all technical and scientific terms used herein have the
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`same meaning as commonly understood by one of ordinary skill in the art. All publications
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`and patents referred to herein are incorporated by reference herein in their entireties.
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`A.
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`Definitions
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`[0053]
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`As used in the specification and the accompanying claims, the indefinite articles
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`"a" and "an" and the definite article "the" include plural as well as singular referents, unless
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`the context clearly dictates otherwise.
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`[0054)
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`The term "about" or "approximately" means an acceptable error for a particular
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`value as determined by one of ordinary skill in the art, which depends in part on how the
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`value is measured or determined. In certain embodiments, the term "about" or
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`"approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the
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`term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%,
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`6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.1 %, or 0.05% of a given value or range.
`
`[0055]
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`As used herein, and