Adaglasib solid pharmaceutical composition

Abstract

Provided are solid pharmaceutical compositions comprising adagrasib suitable for oral administration for treating a subject suffering from cancer; as well as methods for making the compositions and methods for treating cancer.

Description

[Technical Field]

[0001] The present invention relates generally to solid pharmaceutical compositions of adagrasib (2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile); to methods for making these compositions; and to methods for their use to treat various diseases and disorders. [Background technology]

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch, cycling between an inactive (GDP-bound) and an active (TP-bound) state, transducing upstream cellular signals received from multiple tyrosines to downstream effectors that control a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancy was observed over 30 years ago (see, e.g., Santos et al. (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding, leading to constitutive activation of KRas and downstream signaling, have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single-nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the primary amino acid sequence of KRas comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C translocation being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177 (Published online Sep 26, 2012) doi:10.1158 / 1078-0432.CCR-11-3265).

[0004] The role of KRas in malignancies is well known, and the frequent mutations found in KRas in various tumor types have made KRas an extremely attractive target for the pharmaceutical industry to treat cancer. Despite 30 years of extensive research efforts to develop KRas inhibitors for the treatment of cancer, no KRas inhibitors have demonstrated sufficient safety and / or efficacy to gain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21 (8):1797-1801).

[0005] Recently, irreversible covalent inhibitors that target G12C of KRas have been described (see, e.g., Ostrem et al. (2013) Nature 503:548-551). For example, commonly owned and assigned U.S. Provisional Patent Application No. 62 / 586,775 discloses potent, orally bioavailable compounds that irreversibly bind to KRas G12C for treating KRas G12C-mediated cancers.

[0006] A covalent, irreversible inhibitor of KRas G12C is adagrasib (2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile), also known as MRTX849. An amorphous form of this compound was described in Example 478 of International Patent Application PCT / US2018 / 061060, filed November 14, 2018 (published May 23, 2019 as WO2019 / 099524A1), and in Fell et al. (2020) J. Med. Chem. 63, 6679-6693. A crystalline form of this compound was described in International Patent Application PCT / US2021 / 049940, filed September 10, 2021 (published March 17, 2022 as WO2022 / 056307).

[0007] Furthermore, when the formulation is administered to a patient, it is desirable to reduce adverse events (AEs) (also known as side effects), such as nausea, vomiting, and diarrhea.

[0008] Therefore, there is a need for a pharmaceutical composition of adagrasib that exhibits suitable bioavailability and storage stability, is less susceptible to leakage of liquid capsules over time, and has fewer side effects than capsule formulations. Summary of the Invention

[0009] In one embodiment, the present invention provides a pharmaceutical composition in solid form comprising adagrasib or a salt thereof suitable for oral administration to a subject, including, but not limited to, a human subject, wherein after administration to the subject, the solid pharmaceutical composition has a saturation of at least or about 12000 ng of adagrasib under fasted conditions. * hr / mL, and / or under fed conditions at least or approximately 19,000 ng * AUC in hr / mL 0→∞ (area under the curve plotting plasma drug concentration against time)

[0010] In another embodiment, the solid pharmaceutical composition, after administration to a subject, has a saturation of at least or about 12000 ng of adagrasib under fasted conditions. * hr / mL, and / or under fed conditions at least or approximately 19,000 ng * AUC in hr / mL 0→last has the ability to provide.

[0011] In another embodiment, the solid pharmaceutical composition, after administration to a subject, has a C of at least or about 480 ng / mL under fasted conditions and / or at least or about 630 ng / mL under fed conditions for the compound of formula (I). max has the ability to provide.

[0012] In another embodiment, the solid pharmaceutical composition, after administration to a subject, has: a) a saturation of at least or about 12000 ng of adagrasib under fasted conditions; * hr / mL, and / or under fed conditions at least or approximately 19,000 ng * AUC in hr / mL 0→∞ b) for adagrasib, at least or about 12,000 ng under fasting conditions * hr / mL, and / or under fed conditions at least or approximately 19,000 ng * AUC in hr / mL 0→lastand c) for adagrasib, a C of at least about 480 ng / mL under fasted conditions and / or at least about 630 ng / mL under fed conditions. max has the ability to provide.

[0013] In another embodiment, the solid pharmaceutical composition has a T of less than about 6.5 hours, preferably between about 6.0 and 6.25 hours. max to provide.

[0014] In any embodiment, the AUC 0→∞ , AUC 0→last , C max It does not require that the pharmacokinetic (PK) values, etc., mentioned be achieved by administering a single pharmaceutical composition. The present invention contemplates and expressly includes embodiments in which these PK values are achieved after administration of multiple solid pharmaceutical compositions as a single dose (e.g., if a solid pharmaceutical composition (e.g., a tablet) contains 200 mg of adagrasib, then a single dose may include, for example, three such pharmaceutical compositions for a total dose of 600 mg of adagrasib).

[0015] In another embodiment, adagrasib is provided as a salt thereof.

[0016] In another embodiment, the solid pharmaceutical composition comprises, in addition to adagrasib, at least one further anticancer compound.

[0017] In another embodiment, the solid pharmaceutical composition is in the form of a powder or tablet, including an encapsulated powder.

[0018] In another embodiment, the solid pharmaceutical composition is in the form of a tablet.

[0019] In another embodiment, the tablet of the present invention comprises a film coat.

[0020] In another embodiment, a tablet of the present invention comprises adagrasib, one or more diluents, a disintegrant, a glidant, a lubricant, and a film coat.

[0021] In a preferred embodiment, the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, and combinations thereof.

[0022] In another preferred embodiment, the disintegrant comprises crospovidone.

[0023] In another preferred embodiment, the glidant comprises colloidal silicon dioxide.

[0024] In another preferred embodiment, the lubricant comprises magnesium stearate.

[0025] In a preferred embodiment, the tablet of the invention comprises adagrasib, microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate, and a film coat.

[0026] In another embodiment, the solid pharmaceutical composition is provided as a unit dosage form.

[0027] In one embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 200 mg.

[0028] In another embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 300 mg.

[0029] In another embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 400 mg.

[0030] In another embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 600 mg.

[0031] In another embodiment, the composition is in the form of a tablet, (1) adagrasib, which constitutes approximately 30-35 percent (%) of the composition; (2) microcrystalline cellulose, which constitutes approximately 50-55% of the composition; (3) mannitol, which constitutes approximately 8-10% of the composition; (4) crospovidone comprising about 2 to about 5% of the composition; (5) colloidal silicon dioxide constituting up to about 0.5-1.5% of the composition; (6) magnesium stearate, which constitutes about 1-2% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0032] In another embodiment, the composition further comprises a film coat.

[0033] In another embodiment, the composition is in the form of a tablet, (1) adagrasib comprising approximately 30-67 percent (%) of the composition; (2) microcrystalline cellulose, which constitutes approximately 20-55% of the composition; (3) mannitol, comprising about 0-10% of the composition; (4) crospovidone comprising about 2% to about 5% of the composition; (5) colloidal silicon dioxide constituting up to about 0.5-2% of the composition; (6) magnesium stearate, which constitutes about 1-3% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0034] In another embodiment, the composition is in the form of a tablet, (1) adagrasib comprising approximately 50-67 percent (%) of the composition; (2) microcrystalline cellulose, which constitutes approximately 20-45% of the composition; (3) mannitol, comprising about 0-10% of the composition; (4) crospovidone comprising about 2% to about 5% of the composition; (5) colloidal silicon dioxide constituting up to about 0.5-2% of the composition; (6) magnesium stearate, constituting about 1-3% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0035] In a preferred embodiment, the composition of the present invention comprises: (1) adagrasib at approximately 33.3 percent (%) of the composition; (2) microcrystalline cellulose at approximately 51.2% of the composition; (3) mannitol at about 10.0% of the composition; (4) crospovidone at about 3.0% of the composition; (5) colloidal silicon dioxide at about 1.0% of the composition; (6) magnesium stearate at about 1.5% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0036] In another embodiment, the solid pharmaceutical composition comprises: (a) a pre-blending step in which a diluent, a glidant, and adagrasib are blended together; (b) subjecting the components of step (a) to a screening mill to de-lump; (c) blending the ingredients of step (b) with a disintegrant and a glidant; (d) lubricating the ingredients of step (c) by adding a lubricant; (e) dry granulating the ingredients of step (d) using a roller compactor to produce a granulated blend; (f) blending a diluent, a disintegrant, and a glidant with the granulation blend of step (e); (g) lubricating the ingredients of step (f) by adding a lubricant to form a lubricated blend; (h) compressing the lubricated blend of step (g) by loading it into a rotary tablet press and compressing the lubricated blend into core tablets; and (i) A step of film-coating the core tablets of step (h) by loading them into a pan coater and adding a film coating agent. The method is produced by a process including:

[0037] One or more pharmaceutically acceptable excipients (or combinations thereof) may be incorporated as intragranular materials, i.e., incorporated before dry granulation, and / or such excipients may be added to the dry granulated product as extragranular materials, i.e., added after the dry granulated product has been produced.

[0038] In yet another embodiment, the present invention is directed to a method for preparing a solid pharmaceutical composition comprising adagrasib or a salt thereof, wherein the solid pharmaceutical composition is prepared by dry granulation.

[0039] In one embodiment, the method comprises the steps of: (a) a pre-blending step in which a diluent, a glidant, and adagrasib are blended together; (b) subjecting the components of step (a) to a screening mill to de-lump; (c) blending the ingredients of step (b) with a disintegrant and a glidant; (d) lubricating the ingredients of step (c) by adding a lubricant; (e) dry granulating the ingredients of step (d) using a roller compactor to produce a granulated blend; (f) blending a diluent, a disintegrant, and a glidant with the granulation blend of step (e); (g) lubricating the ingredients of step (f) by adding a lubricant to form a lubricated blend; (h) compressing the lubricated blend of step (g) by loading the lubricated blend into a rotary tablet press and compressing the lubricated blend into tablet cores; and (i) A step of film-coating the core tablets of step (h) by loading them into a pan coater and adding a film coating agent. Includes:

[0040] In one embodiment, the solid pharmaceutical composition (e.g., a tablet) may include additional excipients selected from the group consisting of diluents, fillers, superdisintegrants, binders, glidants, lubricants, and combinations thereof.

[0041] In another embodiment, the present invention is directed to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid pharmaceutical composition of the present invention. In one embodiment, the therapeutically effective amount is at least or about 600 mg of adagrasib. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer. In one embodiment, the solid pharmaceutical composition is a tablet.

[0042] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a solid pharmaceutical composition of the present invention. In one embodiment, the solid pharmaceutical composition is a tablet.

[0043] In one embodiment, the provided method for treating cancer causes fewer side effects in a subject than those associated with administering the same amount of a capsule composition of adagrasib. [Brief explanation of the drawings]

[0044] [Figure 1] 1 is a manufacturing process flow diagram illustrating one method for producing a solid pharmaceutical composition of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0045] definition As used herein, the term "adagrasib" refers to a compound of the formula: [ka] The present invention refers to the compound represented by the formula: embedded image and pharmaceutically acceptable salts thereof. The compound has the following chemical name: (2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile). It is also known as MRTX849. The present invention encompasses amorphous and crystalline forms of adagrasib. An amorphous form of this compound is described in Example 478 of International Patent Application PCT / US2018 / 061060, filed November 14, 2018 (published May 23, 2019 as WO2019 / 099524A1), and described in Fell et al. (2020) J. Med. Chem. 63, 6679-6693. A crystalline form of this compound was described in International Patent Application PCT / US2021 / 049940, filed September 10, 2021 (published March 17, 2022 as WO2022 / 056307). Form 1 referred to herein corresponds to Form A in PCT / US2021 / 049940; Form 2 referred to herein corresponds to Form B in PCT / US2021 / 049940. The tablets described herein preferably contain crystalline adagrasib. The contents of these patent applications and references are incorporated herein by reference in their entirety.

[0046] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing an amino acid substitution with cysteine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Cys.

[0047] As used herein, the term "composition" is intended to include a product containing the specified ingredients (and, where indicated, the ingredients in the specified amounts), as well as any product obtained by combining, directly or indirectly, the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the diluent, excipient, or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0048] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent forms of the compounds for purposes of the present invention.

[0049] As used herein, the term "solid state" and related terms refer to crystalline forms, including adagrasib and its various salt forms, unless otherwise specified.

[0050] As used herein, the term "crystalline" and related terms, when used to describe a substance, component, or product, means that the substance, component, or product is crystalline as determined by X-ray diffraction. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA, p. 173 (1990); The United States Pharmacopeia, 23rd ed., pp. 1843-1844 (1995); the contents of which are incorporated herein by reference in their entireties.

[0051] As used herein, the term "crystalline form" and related terms refer to various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof.

[0052] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids. Acid addition salts can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, toluenesulfonic acid, including p-toluenesulfonic acid, m-toluenesulfonic acid, and o-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, eg, Berge et al., J. Pharm. Sci. 66:1-19 (1977)).

[0053] As used herein, the term "amorphous form" refers to a substance in a non-crystalline form.

[0054] As used herein, the terms "polymorph" and "polymorphic form" and related terms refer to crystalline forms of a molecule. Different polymorphs may have different physical properties, such as melting point, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum, as a result of the arrangement or conformation of the molecule in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility, and density (important in formulations and product manufacturing), and dissolution rate (an important factor in bioavailability). Polymorphs of a molecule can be obtained by many methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0055] Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as IR and Raman spectroscopy, solid state NMR, hot stage optical microscopy, differential electron microscopy (SEM), electron crystallographic and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.

[0056] As used herein, the term "solvate" refers to a crystalline form of a substance that contains a solvent. The term "hydrate" refers to a solvate where the solvent is water.

[0057] As used herein, the term "desolvated solvate" refers to a crystalline form of a material that can only be prepared by removing the solvent from a solvate.

[0058] The term "excipient" refers to an inactive ingredient of a pharmaceutical composition of the present invention, including, but not limited to, solvents, wetting agents, diluents, superdisintegrants, binders, glidants, and lubricants.

[0059] As used herein, the terms "treat," "treating," or "treatment" refer to the reduction or amelioration of the progression, severity, and / or duration of a disorder in a subject, the eradication, reduction, or amelioration of symptoms of a disorder, or the delay in the recurrence or onset of a disorder, brought about by the administration of one or more compounds.

[0060] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with a cancer with a KRas G12C mutation (e.g., as measured using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., as measured using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for the KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumor has a KRas G12C mutation (e.g., if the tumor is identified as such using a regulatory-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a KRas G12C mutation (and the clinical records may optionally indicate that the subject should be treated with any of the compositions provided herein).

[0061] As used herein, the term "pediatric patient" refers to a patient under the age of 16 at the time of diagnosis or treatment. The term "child" can be further subdivided into various subpopulations, including neonates (birth to 1 month after birth); infants (1 month to 2 years of age); children (2 years to 12 years of age); and adolescents (12 years to 21 years of age, inclusive, but not including their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE, Nelson Textbook of Pediatrics, 15th ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM et al., Rudolph's Pediatrics, 21st ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd ed. Baltimore: Williams & Wilkins; 1994.

[0062] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample or biopsy sample, e.g., a paraffin-embedded biopsy sample) derived from the patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient with one or more symptoms of a KRas G12C-associated cancer, and / or a patient at high risk of developing a KRas G12C-associated cancer). This may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, assays are typically performed using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0063] The term "regulatory authority" refers to a national agency that approves drugs for medical use in that country. For example, without limitation, an example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0064] As used herein, a "therapeutically effective amount" is an amount sufficient to ameliorate symptoms or in some manner reduce symptoms or halt or reverse the progression of symptoms, or negatively regulate or inhibit the activity of G12C of KRas. Such an amount may be administered in a single dose or, if effective, according to a regimen.

[0065] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0066] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can be attributed to or associated with administration of the composition.

[0067] As used herein, the term "about" or "approximately" refers to an acceptable error in a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0068] The term "fasted state" refers to a state in which a subject has fasted for at least 10 hours prior to administration of the compositions of the present invention.

[0069] The term "fed state" refers to a state in which the composition of the present invention is administered within 30 to 45 minutes after a subject has ingested food.

[0070] As used herein, the term "AUC" refers to the area under the curve plotting plasma drug concentration against time.

[0071] As used herein, "T max " refers to the time after administration of a drug when the maximum plasma concentration is reached.

[0072] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder mediated by or associated with a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0073] Detailed Description of Compositions and Methods The present invention is based on the surprising finding that solid pharmaceutical compositions (e.g., tablets) containing adagrasib, when administered to patients, cause fewer adverse events (AEs, also referred to as "side effects"), such as nausea, vomiting, and diarrhea, than capsule formulations containing the same amount of adagrasib. Without wishing to be bound by any particular theory, it is believed that the lower number of upper GI-related AEs may be due to a higher maximum concentration (C) of adagrasib compared to capsule formulations. max It is speculated that this may be due to the lower GI AEs. Data from ongoing Phase 3 trials indicate that tablet administration also results in fewer upper GI AEs. Another possibility is that the disintegration mechanism and higher density of tablets may result in more rapid clearance of the drug from the stomach. In contrast, capsules may float or adhere to the gastric mucosa, releasing the drug rapidly in the stomach and leading to higher local drug levels. If the drug is gastric irritant, this could result in higher AEs.

[0074] Thus, in one embodiment, the present invention provides a pharmaceutical composition in solid form comprising adagrasib or a salt thereof suitable for oral administration to a subject, including but not limited to a human subject, wherein the solid pharmaceutical composition, after administration to the subject, provides a serotonin concentration of at least or about 12000 ng of adagrasib under fasted conditions. * of time / mL, and / or under fed conditions, at least or about 19,000 ng * AUC in hours / mL 0→∞ (area under the curve plotting plasma drug concentration against time)

[0075] In another embodiment, the solid pharmaceutical composition, after administration to a subject, has a saturation of at least or about 12000 ng of adagrasib under fasted conditions. * hr / mL, and / or under fed conditions at least or approximately 19,000 ng * AUC in hr / mL 0→last has the ability to provide.

[0076] In another embodiment, the solid pharmaceutical composition, after administration to a subject, has a C of at least or about 480 ng / mL under fasted conditions and / or at least or about 630 ng / mL under fed conditions for the compound of formula (I). max has the ability to provide.

[0077] In another embodiment, the solid pharmaceutical composition, after administration to a subject, has: a) a saturation of at least or about 12000 ng of adagrasib under fasted conditions; * hr / mL, and / or under fed conditions at least or approximately 19,000 ng * AUC in hr / mL 0→∞ b) for adagrasib, at least or about 12,000 ng under fasting conditions * hr / mL, and / or under fed conditions at least or approximately 19,000 ng * AUC in hr / mL 0→lastand c) for adagrasib, a C of at least about 480 ng / mL under fasted conditions and / or at least about 630 ng / mL under fed conditions. max has the ability to provide.

[0078] In another embodiment, the solid pharmaceutical composition has a T of less than about 6.5 hours, preferably between about 6.0 and 6.25 hours. max to provide.

[0079] In any embodiment, the AUC 0→∞ , AUC 0→last , C max It is not required that the pharmacokinetic (PK) values, such as those mentioned, be achieved by administering a single pharmaceutical composition. The present invention contemplates and expressly includes embodiments in which these PK values are achieved after administering multiple solid pharmaceutical compositions as a single dose (e.g., if a solid pharmaceutical composition (e.g., a tablet) contains 200 mg of adagrasib, a single dose may include, for example, three such pharmaceutical compositions for a total dose of 600 mg of adagrasib).

[0080] In another embodiment, adagrasib is present as its salt.

[0081] In another embodiment, the solid pharmaceutical composition comprises, in addition to adagrasib, at least one further anticancer compound.

[0082] In another embodiment, the solid pharmaceutical composition is in the form of a powder or tablet, including an encapsulated powder.

[0083] In another embodiment, the solid pharmaceutical composition is in the form of a tablet.

[0084] In one embodiment, the solid pharmaceutical composition (e.g., a tablet) may include various excipients selected from the group consisting of solvents, wetting agents, diluents, fillers, superdisintegrants, binders, glidants, lubricants, and combinations thereof. It should be understood that the present invention contemplates the use of other excipients that serve substantially the same functions in substantially the same manner as described above.

[0085] Tablets may contain the solid active ingredient in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of tablets, which may be, for example, a disintegrant, such as a superdisintegrant; a binder; a diluent; a glidant; a lubricant; an emulsifier; or any other excipient known to those skilled in the art.

[0086] Preferred tablets are those that provide good potency, content uniformity, hardness, friability, and dissolution, and contribute to the chemical and physical stability of the pharmaceutical composition.

[0087] In another embodiment, the tablet of the present invention comprises a film coat.

[0088] In another embodiment, a tablet of the present invention comprises adagrasib, one or more diluents, a disintegrant, a glidant, a lubricant, and a film coat.

[0089] In a preferred embodiment, the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, and combinations thereof.

[0090] In another preferred embodiment, the disintegrant comprises crospovidone.

[0091] In another preferred embodiment, the glidant comprises colloidal silicon dioxide.

[0092] In another preferred embodiment, the lubricant comprises magnesium stearate.

[0093] In a preferred embodiment, the tablet of the invention comprises adagrasib, microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate, and a film coat.

[0094] In another embodiment, the solid pharmaceutical composition is provided as a unit dosage form.

[0095] In one embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 200 mg.

[0096] In another embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 300 mg.

[0097] In another embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 400 mg.

[0098] In another embodiment, the amount of adagrasib in the solid pharmaceutical composition is at least or about 600 mg.

[0099] In another embodiment, the composition is in the form of a tablet, (1) adagrasib, which constitutes approximately 30-35 percent (%) of the composition; (2) microcrystalline cellulose, which constitutes approximately 50-55% of the composition; (3) mannitol, which constitutes approximately 8-10% of the composition; (4) crospovidone comprising about 2% to about 5% of the composition; (5) colloidal silicon dioxide constituting up to about 0.5-1.5% of the composition; (6) magnesium stearate, which constitutes about 1-2% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0100] In another embodiment, the composition is in the form of a tablet, (1) adagrasib comprising approximately 30-67 percent (%) of the composition; (2) microcrystalline cellulose, which constitutes approximately 20-45% of the composition; (3) mannitol, comprising about 0-10% of the composition; (4) crospovidone comprising about 2 to about 5% of the composition; (5) colloidal silicon dioxide constituting up to about 0.5-2% of the composition; (6) magnesium stearate, which constitutes about 1-3% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0101] In another embodiment, the composition is in the form of a tablet, (1) adagrasib comprising approximately 50-67 percent (%) of the composition; (2) microcrystalline cellulose, which constitutes approximately 20-45% of the composition; (3) mannitol, comprising about 0-10% of the composition; (4) crospovidone comprising about 2 to about 5% of the composition; (5) colloidal silicon dioxide constituting up to about 0.5-2% of the composition; (6) magnesium stearate, which constitutes about 1-3% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0102] In another embodiment, the composition further comprises a film coat.

[0103] In a preferred embodiment, the composition of the present invention (1) adagrasib at approximately 33.3 percent (%) of the composition; (2) microcrystalline cellulose at approximately 51.2% of the composition; (3) mannitol at about 10.0% of the composition; (4) crospovidone at about 3.0% of the composition; (5) colloidal silicon dioxide at about 1.0% of the composition; and (6) magnesium stearate at about 1.5% of the composition; Here, all percentages are by weight, with the total weight being 100%.

[0104] In another embodiment, the solid pharmaceutical composition comprises: (a) a pre-blending step in which a diluent, a glidant, and adagrasib are blended together; (b) subjecting the components of step (a) to a screening mill to de-lump; (c) blending the ingredients of step (b) with a disintegrant and a glidant; (d) lubricating the ingredients of step (c) by adding a lubricant; (e) dry granulating the ingredients of step (d) using a roller compactor to produce a granulated blend; (f) blending a diluent, a disintegrant, and a glidant with the granulation blend of step (e); (g) lubricating the ingredients of step (f) by adding a lubricant to form a lubricated blend; (h) compressing the lubricated blend of step (g) by loading the lubricated blend into a rotary tablet press and compressing the lubricated blend into tablet cores; and (i) A step of film-coating the core tablets of step (h) by loading them into a pan coater and adding a film coating agent. The method is produced by a process including:

[0105] One or more pharmaceutically acceptable excipients (or combinations thereof) may be incorporated as intragranular materials, i.e., incorporated before dry granulation; and / or such excipients may be added to the dry granulated product as extragranular materials, i.e., added after the dry granulated product has been dried.

[0106] In yet another embodiment, the present invention is directed to a method for preparing a solid pharmaceutical composition comprising adagrasib or a salt thereof, wherein the solid pharmaceutical composition is prepared by dry granulation.

[0107] In one embodiment, the method comprises: (a) pre-blending, blending together a diluent, a glidant, and adagrasib; (b) de-lumping the components of step (a) using a screening mill; (c) blending the ingredients of step (b) with a disintegrant and a glidant; (d) adding a lubricant to step (c) to perform intragranular lubrication; (e) dry granulating the ingredients of step (d) using a roller compactor to produce a granulated blend; (f) blending a diluent, a disintegrant, and a glidant with the granulation blend of step (e); (g) intragranular lubrication by adding a lubricant to the ingredients of step (f) to form a lubricated blend; (h) compressing the lubricated blend of step (g) by loading the lubricated blend into a rotary tablet press and compressing the lubricated blend into tablet cores; (i) adding a film coating agent to the tablet cores of step (h); Includes:

[0108] The pharmaceutical compositions provided herein may further comprise one or more pharmaceutically acceptable excipients such as suspending agents, flavoring agents, sweetening agents, dispersing agents, surfactants, coloring agents, solubilizing agents, wetting agents, plasticizers, stabilizers, penetration enhancers, antifoaming agents, antioxidants, preservatives, or mixtures thereof.

[0109] In another embodiment, the present invention is directed to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid pharmaceutical composition of the present invention. In one embodiment, the therapeutically effective amount is at least or about 600 mg of adagrasib. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer. In one embodiment, the solid pharmaceutical composition is a tablet.

[0110] Also provided herein is a method of treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as measured using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a solid pharmaceutical composition of the present invention. In one embodiment, the solid pharmaceutical composition is a tablet.

[0111] In one embodiment, the provided method of treating cancer causes fewer side effects in a subject than those associated with administering the same amount of a capsule composition of adagrasib.

[0112] However, it will be understood that the specific dose level and frequency of administration for a particular patient may vary and will depend upon a variety of factors including, for example, the activity of the particular polymorph utilized, the metabolic stability and duration of action of that polymorph, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, and the severity of the patient's condition.

[0113] The pharmaceutical compositions provided herein can be combined with other compounds that have utility in the treatment or prevention of cancer. In many cases, administering the pharmaceutical composition to a subject in combination with these alternative drugs enhances the efficacy of such drugs. Thus, in some cases, the pharmaceutical compositions of the present invention, when combined with or administered in combination with, for example, an anti-cancer drug, can be used in a lower dosage than would be expected if used alone, or in a lower dosage than calculated for combination therapy.

[0114] High drug-loaded formulations with drug loads greater than 50%, with and without mannitol, have been successfully evaluated for their processability, in vitro solubility, and bioavailability in a preclinical species (canine model). Formulations with drug loads up to 67% have been evaluated successfully, and the amount of mannitol has been observed to affect both processability and bioavailability. Decreasing the w / w% of mannitol from 10% w / w to 5% w / w and 0% w / w has been found to increase drug bioavailability and improve processability.

[0115] Examples of the present invention The present invention will now be described with reference to examples. Example 1: Adaglasib formulation This example describes the formulation of adagrasib tablets, which was manufactured and tested for bioavailability and food effect.

[0116] The tablets are immediate-release (IR) film-coated tablets for oral administration. Each tablet contains 200 mg or 300 mg, or 400 mg or 600 mg of the active agent (adagrasib). The qualitative and quantitative composition per unit of the drug product is shown in Tables 1 to 9. No excessive amounts are used in the drug product.

[0117] Table 1 Qualitative and quantitative unit composition of 200 mg (33% (w / w)) of medicinal products [Table 1]

[0118] Table 2 Qualitative and quantitative unit composition of 300-600mg (50-67% (w / w)) of medicinal products [Table 2]

[0119] Table 3 Qualitative and quantitative unit composition of 300 mg (50% (w / w)) of medicinal products [Table 3]

[0120] Table 4 Qualitative and quantitative unit composition of 400 mg (50% (w / w)) of medical product [Table 4]

[0121] Table 5 Qualitative and quantitative unit composition of 300 mg (50% (w / w)) of medicinal products [Table 5]

[0122] Table 6 Qualitative and quantitative unit composition of 400 mg (50% (w / w)) of medical product [Table 6]

[0123] Table 7 Qualitative and quantitative unit composition of 300mg (57.14% (w / w)) of medicinal product [Table 7]

[0124] Table 8 Qualitative and quantitative unit composition of 400mg (57.14% (w / w)) of medical product [Table 8]

[0125] Table 9 Qualitative and quantitative unit composition of 600mg (66.67% (w / w)) of medical product [Table 9]

[0126] Example 2: Pharmacokinetics The primary objectives of the study were to investigate the relative bioavailability (BA) and pharmacokinetic (PK) profiles of MRTX849 (i.e., adagrasib) in capsule and tablet formulations after single-dose oral administration to healthy subjects under fasting conditions, to evaluate the effect of food on the PK profile of MRTX849 in tablet formulation after single-dose oral administration to healthy subjects, and to evaluate side effects.

[0127] The secondary objective of the study was to investigate the safety and tolerability, including the incidence of adverse events (side effects), of single-dose oral administration of capsule and tablet formulations of MRTX849 in healthy subjects under fasting and fed conditions.

[0128] Finally, an exploratory objective of the study was to investigate the PK profiles of potential MRTX849 metabolites following single oral dose administration of MRTX849 capsule and tablet formulations in healthy subjects under fasted and fed conditions.

[0129] methodology

[0130] This study was a phase 1, randomized, open-label, 2x2 crossover trial in healthy subjects, consisting of two parts. In part 1, 38 subjects were enrolled and received a single oral dose of 600 mg adagrasib in capsule (reference [R]) or tablet (test [T]) formulation under fasting conditions in one of two randomized treatment sequences (RT or TR).

[0131] In Part 2, 20 subjects were enrolled to receive a 600 mg dose of adagrasib in three 200 mg tablets under fasted (R) or fed (high-fat, high-calorie meal; T) conditions in one of two randomized treatment sequences (RT or TR). Treatments within a sequence were separated by a washout period of 9 to 12 days. Serial pharmacokinetic (PK) blood samples were collected from pre-dose through 168 hours post-dose. Noncompartmental analysis was performed to evaluate key PK parameters (C max , AUC last , and AUC ∞ ) were derived. Log-transformed PK parameters were analyzed with a mixed-effects model, including treatment, period, and sequence as fixed effects and subject nested within sequence as a random effect. For each PK parameter, a point estimate and its associated 90% confidence interval (CI) were constructed for the treatment difference between the T and R treatments (i.e., tablet vs. capsule, fed vs. fasted), and this difference and its 90% CI were exponentiated to obtain the geometric least squares mean (GLSM) and its 90% CI ratio.

[0132] result

[0133] In Part 1, 35 subjects provided evaluable PK data for statistical analysis. The relative BA of the tablet formulation was approximately 89% compared to the capsule formulation. max , AUC last , and AUC ∞ The GLSM rates (90% CI) for were 86.47% (77.53%-96.43%), 88.82% (79.87%-98.78%), and 88.90% (79.98%-98.81%), respectively.

[0134] In Part 2, 15 subjects provided evaluable PK data for statistical analysis. Food significantly increased the C of the tablet formulation. max and AUC increased by approximately 20% and 38%, respectively. max , AUC last , and AUC ∞The GLSM rates (90% CI) for adagrasib were 120.33% (95.27%-151.99%), 137.64% (113.86%-166.37%), and 137.53% (113.85%-166.12%), respectively. Adaglasib was generally well tolerated, with gastrointestinal (GI) symptoms being the most frequently reported. Diarrhea, nausea, and vomiting were less frequent with the tablet vs. capsule formulation (19.4% vs. 35.1%, 13.9% vs. 32.4%, and 0% vs. 2.7%, respectively) and with the tablet in the fed vs. fasted state (12.5% vs. 47.4%, 6.3% vs. 36.8%, and 0% vs. 21.1%, respectively).

[0135] Table 10 shows the results of a single-dose bioavailability study of 600 mg adagrasib combination capsules (reference) and combination tablets (Study 1) under fasting conditions. Table 10 Statistical Analysis of MRTX849 Primary Pharmacokinetic Endpoints to Evaluate the Relative Bioavailability of a Single Dose of 600 mg MRTX849 Combination Capsules (Reference) and Combination Tablets (Study 1) Under Fasted Conditions [Table 10] AUC ∞ = area under the plasma concentration-time curve from time 0 to infinity; AUC last = area under the curve from time 0 to the time of the last measurable concentration; CI = confidence interval; C max = maximum (peak) plasma drug concentration; GLSM = geometric least squares mean; ln = natural logarithm; n = number of subjects with valid observations; R: 600 mg MRTX849 combined capsules (reference); T1: 600 mg MRTX849 combined tablets (Interim Study 1); Model: ln(PK parameters) = sequence + treatment (R and T1) + random error (subject fitted as random effect); degrees of freedom method = KR In each model, data for the reference and test drugs were included exclusively. Proportions and corresponding confidence limits (expressed as %) were back-transformed from the differences and confidence limits calculated on a logarithmic scale. Only subjects with valid PK parameters for both treatments were included in the statistical analysis.

[0136] Table 10 shows that the relative BA of the combination tablet formulation was approximately 5% lower than that of the combination capsule formulation. The combination capsules and tablets contain a mixture of crystalline forms of adagrasib, Form 1 and Form 2. The primary PK parameters of MRTX849 (C max , AUC last , and AUC ∞ Bioequivalence was demonstrated for the combination tablet vs. combination capsule and Form 2 capsule vs. combination capsule, as the 90% CI of the GLSM proportions of (1) was within the regulatory BE limits of 80.00% to 125.00%. Intrasubject variability was less than 25%.

[0137] Table 11 provides a summary of the PK parameters for adagrasib in plasma. Table 11 Summary of MRTX849 Pharmacokinetic Parameters Following Single Administration of 600 mg MRTX849 Combination Capsules (Reference), Combination Tablets (Study 1), and Form 2 Capsules (Study 2) Under Fasted Conditions [Table 11] AUC ∞ = area under the plasma concentration-time curve from time 0 to infinity; AUC last = time from time 0 to the last quantifiable concentration (t last ) area under the concentration-time curve; CL / F = apparent total clearance of drug from plasma after oral administration; C max = maximum (peak) plasma drug concentration; CV = coefficient of variation (%); n = number of subjects with valid observations; N = number of subjects; NC = not calculated; t 1 / 2 = elimination half-life; t max = time to reach maximum (peak) plasma concentration after administration of the drug; V z / F = apparent volume of distribution during the terminal phase after non-intravenous administration; statistical representation of geometric mean (CV) [n]; t max For , display the statistical value of median (min-max) [n]; t 1 / 2 For the arithmetic mean (arithmetic CV) statistical value display

[0138] Table 12 also summarizes the PK parameters of adagrasib in plasma. Table 12 Summary of MRTX849 pharmacokinetic parameters after single administration of 600 mg MRTX849 combination capsules (reference) and Form 2 tablets (test) under fasting conditions [Table 12] AUC ∞ = area under the plasma concentration-time curve from time 0 to infinity; AUC last = time from time 0 to the last quantifiable concentration (t last ) area under the concentration-time curve; CL / F = apparent total clearance of drug from plasma after oral administration; C max = maximum (peak) plasma drug concentration; CV = coefficient of variation (%); n = number of subjects with valid observations; N = number of subjects; NC = not calculated; t 1 / 2 = elimination half-life; t max = time to reach maximum (peak) plasma concentration after administration of the drug; V z / F = apparent volume of distribution during the terminal phase after non-intravenous administration; statistical representation of geometric mean (CV) [n]; t max For , display the statistical value of median (min-max) [n]; t 1 / 2 For the arithmetic mean (arithmetic CV) statistical value display

[0139] Table 13 shows the statistical analysis for the evaluation of the relative BA of 600 mg MRTX849 combined (reference) and Form 2 tablets (test) based on the primary PK parameters of MRTX849. Table 13 Statistical Analysis of MRTX849 Primary Pharmacokinetic Endpoints to Evaluate the Relative Bioavailability of a Single Dose of 600 mg MRTX849 Combined Capsules (Reference) and Form 2 Tablets (Test) Under Fasted Conditions [Table 13] AUC ∞ = area under the plasma concentration-time curve from time 0 to infinity; AUC last = area under the curve from time 0 to the time of the last measurable concentration; CI = confidence interval; C max = maximum (peak) plasma drug concentration; GLSM = geometric least squares mean; ln = natural logarithm; n = number of subjects with valid observations; R: 600 mg MRTX849 combined capsules (reference); T: 600 mg MRTX849 form 2 tablets (test); Model: ln(PK parameters) = sequence + period + treatment + random error (subjects fitted as random effects); degrees of freedom method = KR Proportions and corresponding confidence limits (expressed as %) were back-transformed from the differences and confidence limits calculated on a logarithmic scale.

[0140] The results showed that the relative BA of Form 2 tablets was about 89% compared to the combined capsules based on AUC (Table 11). However, the BE between Form 2 tablets and combined capsules was about 89%. max , AUC last , and AUC ∞ The upper limit of the 90% CI for the GLSM proportion of C was not within the regulatory BE limit of 80.00% to 125.00%. The upper limit of the 90% CI for the primary PK parameter was within the BE limit of 125.00%, but the upper limit of the 90% CI for C max , AUC last , and AUC ∞ The lower limits of the 90% CIs of (77.53%, 79.87%, and 79.98%, respectively) were slightly below the lower limit of the 80.00% BE limit.

[0141] The effect of diet was investigated as part of the study.

[0142] Eligible subjects were randomly assigned to one of two treatment sequences. In Periods 1 and 2, eligible subjects entered the Clinical Research Unit (CRU) on Day 1 and remained there until discharge on Day 8. A single dose of 600 mg of MRTX849 (Form 2 tablets) was administered under fasting conditions or with a high-fat, high-calorie breakfast on Day 1 of each of Periods 1 and 2. The MRTX849 dose was determined based on preliminary results from Part 1. Each period included serial blood draws obtained pre-dose through 168 hours post-dose for analysis of plasma concentrations of MRTX849 (and metabolites, if applicable). A washout period of 9 to 12 days was required after the administration of the dose in Period 1. A follow-up telephone call was scheduled between 2 and 5 days (inclusive) after the completion of Period 2.

[0143] The results showed that a high-fat, high-calorie meal significantly reduced the C of MRTX849 Form 2 tablets. max The results showed that the Cmax and AUC increased by approximately 20% and 38%, respectively (see Table 14). The efficacy and safety profile of MRTX849 in patients was characterized using the combination capsule under fasting conditions. Considering the relative BA of the Form 2 tablet compared to the combination capsule, it is expected that the Form 2 tablet under fed conditions would result in an approximately 4% higher Cmax and a 22% higher AUC compared to the combination capsule under fasting conditions. Furthermore, the Form 2 tablet under fed conditions showed less inter-subject variability than under fasting conditions, potentially resulting in less variability in subject clinical response. Therefore, the effect of food on MRTX849 Form 2 tablets is not considered clinically meaningful.

[0144] Table 14 Statistical Analysis of MRTX849 Primary Pharmacokinetic Endpoints to Evaluate the Effect of Food on a Single 600mg Dose of MRTX849 Form 2 Tablets [Table 14] AUC ∞= area under the plasma concentration-time curve from time 0 to infinity; AUC last = area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration; CI = confidence interval; C max = maximum (peak) plasma drug concentration; GLSM = geometric least squares mean; ln = natural logarithm; n = number of subjects with valid observations; R: 600 mg MRTX849 Form 2 tablets, fasted state (reference); T: 600 mg MRTX849 Form 2 tablets, fed state (test); Model: ln(PK parameters) = sequence + period + treatment + random error (subjects fitted as random effects); Proportions and corresponding confidence limits (expressed as %) were back-transformed from the differences and confidence limits calculated on a logarithmic scale. Only subjects with data for both treatments (fasted and fed) are included in the statistical analysis.

[0145] side effects Gastrointestinal disturbances, particularly diarrhea, nausea, and vomiting, appeared to occur less frequently during tablet administration compared with capsule administration, and gastrointestinal disturbances, particularly diarrhea, nausea, abdominal pain, and vomiting, appeared to occur less frequently when tablets were taken with food compared with the fasting state.

[0146] A summary of adverse reactions is shown in Table 15. Table 15 Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term [Table 15] F2 = Form 2; MF = Mixed; nS = Number of subjects showing adverse events; N = Number of subjects; % = Percent of subjects showing valid observations (nS / N x 100). Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0. Treatment-emergent adverse events (TEAEs) were defined as adverse events that occurred during or after dosing, or that occurred before dosing and increased in severity after dosing.

[0147] Example 3: Tablet manufacturing method This example demonstrates an exemplary method for preparing adagrasib tablets.

[0148] FIG. 1 depicts a flow diagram of a manufacturing process that can be used to prepare the solid dosage forms of the present invention.

[0149] The manufacturing method is described as follows.

[0150] Pre-blending (Stage 1) 1. Charge a portion of the microcrystalline cellulose and a portion of the colloidal silicon dioxide to a blender and blend the ingredients.

[0151] Pre-blending (Stage 2) 2. Charge the adagrasib drug, a portion of the microcrystalline cellulose, and mannitol into the same blender and blend the ingredients.

[0152] Removal of lumps 3. Removal of component agglomerates using a conical screening mill

[0153] Intragranular Blending 4. Charge a portion of the crospovidone and a portion of the colloidal silicon dioxide (0.5% w / w) into the same blender and blend the ingredients.

[0154] Intragranular lubrication 5. Charge a portion of the magnesium stearate into the same blender and blend the ingredients.

[0155] Dry granulation (roller compaction) 6. Charge the ingredients from step 9 into a roller compactor connected to a vibratory mill to granulate the blend.

[0156] Extragranular Blending 7. Charge a portion of the microcrystalline cellulose, a portion of the crospovidone, and a portion of the colloidal silicon dioxide into the blender containing the granulated blend and blend the ingredients.

[0157] extragranular lubrication 8. Charge a portion of the magnesium stearate into a blender and blend the ingredients.

[0158] compression 9. The final lubricated blend is loaded into a rotary tablet press and the blend is compressed into tablet cores. 10. The core tablet product is subjected to dust removal and metal detection.

[0159] In-process management: Tablet appearance, weight, and hardness are monitored and controlled throughout the compression process.

[0160] Film Coating 11. Prepare an aqueous suspension of film coating agent and purified water using a mixer and an appropriately sized container. 12. Load the core tablets into a perforated pan coater and coat the tablets by spraying with the suspension from the previous step until a 3-4% weight gain is achieved.

[0161] All publications and patent applications cited in this specification are herein incorporated by name to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Although the foregoing description has been set forth in some detail in the detailed description and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art in light of the teachings of the specification that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. (1) adagrasib comprising approximately 30-67 percent (%) of the composition; (2) microcrystalline cellulose, which constitutes approximately 30-55% of the composition; (3) Mannitol, comprising about 0-10% of the composition; (4) crospovidone, comprising about 2% to about 5% of the composition; (5) colloidal silicon dioxide, comprising about 0.5-2% of the composition; and (6) magnesium stearate, comprising about 1-3% of the composition; where all percentages are by weight and the total weight is 100%. Solid pharmaceutical compositions.

2. 10. The solid pharmaceutical composition of claim 1, wherein the solid pharmaceutical composition is in the form of a tablet.

3. 10. The solid pharmaceutical composition of claim 1, wherein the solid pharmaceutical composition further comprises a film coat.

4. (1) adagrasib comprises approximately 33.3 percent (%) of the composition; (2) microcrystalline cellulose comprises approximately 51.2% of the composition; (3) mannitol comprises about 10% of the composition; (4) crospovidone comprises about 3% of the composition; (5) colloidal silicon dioxide comprises about 1% of the composition; (6) magnesium stearate comprises about 1.5% of the composition; where all percentages are by weight and the total weight is 100%. The solid pharmaceutical composition according to claim 1.

5. 5. The solid pharmaceutical composition according to claim 4, wherein the solid pharmaceutical composition is in the form of a tablet.

6. 6. The solid pharmaceutical composition of claim 5, wherein the solid pharmaceutical composition further comprises a film coat.

7. (1) adagrasib, which comprises approximately 33.3 percent (%) of the composition; (2) microcrystalline cellulose, comprising approximately 51.2% of the composition; (3) mannitol, comprising about 10.0% of the composition; (4) Crospovidone, comprising about 3.0% of the composition; (5) colloidal silicon dioxide, comprising approximately 1.0% of the composition; and (6) Magnesium stearate, which constitutes approximately 1.5% of the composition.

1. An oral solid pharmaceutical composition in the form of a tablet, comprising:

8. (1) adagrasib comprises approximately 57.1 percent (%) of the composition; (2) microcrystalline cellulose comprises approximately 36.4% of the composition; (3) mannitol comprises about 0% of the composition; (4) crospovidone comprises about 3% of the composition; (5) colloidal silicon dioxide comprises about 2% of the composition; (6) magnesium stearate comprises about 1.5% of the composition; where all percentages are by weight and the total weight is 100%. The solid pharmaceutical composition according to claim 1.

9. 9. The solid pharmaceutical composition of claim 8, in the form of a tablet.

10. (1) adagrasib comprises about 50 percent (%) of the composition; (2) microcrystalline cellulose comprises approximately 37% of the composition; (3) mannitol comprises about 5% of the composition; (4) crospovidone comprises about 5% of the composition; (5) colloidal silicon dioxide comprises about 1% of the composition; (6) magnesium stearate comprises about 2% of the composition; where all percentages are by weight and the total weight is 100%. The solid pharmaceutical composition according to claim 1.

11. 11. The solid pharmaceutical composition of claim 10, in the form of a tablet.

12. After administration to the subject, adagrasib has a fasting concentration of at least or about 12,000 ng ＊ hr / mL and / or at least about 19,000 ng under fed conditions ＊ AUC in hr / mL ０→∞ The solid pharmaceutical composition according to any one of claims 1 to 11, which is capable of providing:

13. After administration to the subject, adagrasib has a fasting concentration of at least or about 12,000 ng ＊ hr / mL and / or at least about 19,000 ng under fed conditions ＊ AUC in hr / mL ０→ｌａｓｔ The solid pharmaceutical composition according to any one of claims 1 to 12, which is capable of providing:

14. After administration to a subject, adagrasib has a C of at least about 480 ng / mL under fasted conditions and / or at least about 630 ng / mL under fed conditions. ｍａｘ The solid pharmaceutical composition according to any one of claims 1 to 13, which is capable of providing:

15. After administration to the subject, a) for adagrasib, at least or about 12,000 ng / mL under fasting conditions ＊ hr / mL and / or at least about 19,000 ng under fed conditions ＊ AUC in hr / mL ０→∞ b) for adagrasib, at least or about 12,000 ng under fasting conditions ＊ hr / mL and / or at least about 19,000 ng under fed conditions ＊ AUC in hr / mL ０→ｌａｓｔ and c) for adagrasib, a C of at least about 480 ng / mL under fasted conditions and / or at least about 630 ng / mL under fed conditions. ｍａｘ The solid pharmaceutical composition according to any one of claims 1 to 14, which is capable of providing:

16. The solid pharmaceutical composition according to any one of claims 1 to 15, wherein adagrasib is present as a salt thereof.

17. The solid pharmaceutical composition according to any one of claims 1 to 16, comprising, in addition to adagrasib, at least one further anticancer compound.

18. The solid pharmaceutical composition according to any one of claims 1 to 17, provided in unit dosage form.

19. 19. The solid pharmaceutical composition according to any one of claims 1 to 18, wherein the amount of adagrasib in the solid pharmaceutical composition is at least or about 200 mg.

20. 19. The solid pharmaceutical composition according to any one of claims 1 to 18, wherein the amount of adagrasib in the solid pharmaceutical composition is at least or about 300 mg.

21. 19. The solid pharmaceutical composition according to any one of claims 1 to 18, wherein the amount of adagrasib in the solid pharmaceutical composition is at least or about 400 mg.

22. 19. The solid pharmaceutical composition according to any one of claims 1 to 18, wherein the amount of adagrasib in the solid pharmaceutical composition is at least or about 600 mg.

23. (a) a pre-blending step in which a diluent, a glidant, and adagrasib are blended together; (b) subjecting the components of step (a) to a screening mill to de-lump; (c) blending the ingredients of step (b) with a disintegrant and a glidant; (d) lubricating the ingredients of step (c) by adding a lubricant; (e) dry granulating the ingredients of step (d) using a roller compactor to produce a granulated blend; (f) blending a diluent, a disintegrant, and a glidant with the granulation blend of step (e); (g) lubricating the ingredients of step (f) by adding a lubricant to form a lubricated blend; (h) compressing the lubricated blend of step (g) into a rotary tablet press by compressing the lubricated blend into tablet cores; and (i) A step of film-coating the core tablets of step (h) by loading them into a pan coater and adding a film coating agent.

1. A solid pharmaceutical composition comprising adagrasib, the solid pharmaceutical composition being manufactured by a process comprising:

24. The method for producing a solid pharmaceutical composition according to any one of claims 1 to 23, wherein the solid pharmaceutical composition is produced by dry granulation.

25. (a) a pre-blending step in which a diluent, a glidant, and adagrasib are blended together; (b) subjecting the components of step (a) to a screening mill to de-lump; (c) blending the ingredients of step (b) with a disintegrant and a glidant; (d) lubricating the ingredients of step (c) by adding a lubricant; (e) dry granulating the ingredients of step (d) using a roller compactor to produce a granulated blend; (f) blending a diluent, a disintegrant, and a glidant with the granulation blend of step (e); (g) lubricating the ingredients of step (f) by adding a lubricant to form a lubricated blend; (h) compressing the lubricated blend of step (g) into a rotary tablet press by compressing the lubricated blend into tablet cores; and A step of film-coating the core tablets of step (h) by loading them into a pan coater and adding a film coating agent.

25. The method of claim 24, comprising:

26. 24. A method for treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a solid pharmaceutical composition according to any one of claims 1 to 23.

27. 27. The method of claim 26, wherein the therapeutically effective amount is at least or about 600 mg of adagrasib.

28. 27. The method of claim 26, wherein the cancer is a KRas G12C-associated cancer.

29. 27. The method of claim 26, wherein the cancer is lung cancer.

30. 27. The method of claim 26, wherein the side effect of nausea in the subject is less than the side effect of nausea associated with administration of the same amount of a capsule composition of adagrasib.

31. 27. The method of claim 26, wherein the emetic side effect in the subject is less than the emetic side effect associated with administration of the same amount of a capsule composition of adagrasib.

32. 27. The method of claim 26, wherein the diarrhea side effect in the subject is less than the diarrhea side effect associated with administration of the same amount of a capsule composition of adagrasib.

33. 27. The method of claim 26, wherein the side effect of nausea in the subject occurs in less than 17% of the overall subject population.

34. 27. The method of claim 26, wherein the emetic side effect in the subject occurs in less than 5% of the overall subject population.

35. 27. The method of claim 26, wherein the side effect of diarrhea in the subject occurs in less than 20% of the overall subject population.

36. 24. A method of treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a G12C mutation in KRas; and (b) administering to the subject a therapeutically effective amount of the solid pharmaceutical composition of any one of claims 1 to 23.

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