WO2019225467A1 - Composition pharmaceutique contenant de l'apixaban à faible dose - Google Patents

Composition pharmaceutique contenant de l'apixaban à faible dose Download PDF

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WO2019225467A1
WO2019225467A1 PCT/JP2019/019479 JP2019019479W WO2019225467A1 WO 2019225467 A1 WO2019225467 A1 WO 2019225467A1 JP 2019019479 W JP2019019479 W JP 2019019479W WO 2019225467 A1 WO2019225467 A1 WO 2019225467A1
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patient
apixaban
blood
pharmaceutical composition
pharmaceutically acceptable
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PCT/JP2019/019479
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English (en)
Japanese (ja)
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原　正彦
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株式会社 Ｒｅｓｅａｒｃｈ Ｍｉｎｄ
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Publication of WO2019225467A1 publication Critical patent/WO2019225467A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a pharmaceutical composition containing a low dose of apixaban and a method for administering apixaban.
  • the present invention relates to at least two of the following criteria: (1) Age 80 years or older; (2) Body weight 60 kg or less; and (3) Serum creatinine concentration 1.5 kg mg / dl or more.
  • the present invention relates to a pharmaceutical composition containing a low-dose apixaban and a method for administering apixaban for the patient concerned.
  • Apixaban is one of the known oral anticoagulants that target factor Xa.
  • apixaban is marketed under the trade name Eliquis (registered trademark), and is mainly used as an inhibitor of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, as well as venous thromboembolism (Depth). Venous thrombosis and pulmonary thromboembolism) and used as a recurrence inhibitor.
  • Non-patent Document 1 Non-patent Document 1
  • the present invention has atrial fibrillation and corresponds to at least two of criteria (1) age 80 years and older; (2) body weight 60 kg or less; and (3) serum creatinine concentration 1.5 kg / dl or more
  • An object of the present invention is to provide a pharmaceutical composition comprising apixaban and a method for administering apixaban, which is intended for patients and reduces or does not cause adverse side effects such as bleeding and accompanying complications.
  • the present inventor has focused on the blood trough value of apixaban.
  • the present inventor has an effective blood trough value that exhibits a therapeutic or preventive effect and does not cause harmful side effects, It was found to be about 50 ng / mL to about 90 ng / mL.
  • the high-risk group in order to maintain this blood trough value, it was found that about 0.8 to 1.5 mg of apixaban should be administered twice or three times a day. This was a totally unexpected result because administration of apixaban less than 2.5 mg / dose was considered to have no therapeutic effect.
  • the present invention is a pharmaceutical composition for inhibiting blood coagulation in a patient or treating or preventing a disease or disorder caused by blood coagulation, comprising apixaban or a pharmaceutically acceptable salt or solvate thereof.
  • apixaban or a pharmaceutically acceptable salt or solvate thereof is used to be administered to the patient twice or three times a day.
  • the pharmaceutical composition wherein the patient has atrial fibrillation and meets at least two of the following criteria (1) to (3): Criteria (1) Age 80 and over; (2) Weight 60 kg or less; (3) Serum creatinine concentration of 1.5 mg / dl or more.
  • the invention also treats a disease or disorder caused by blood coagulation or inhibiting a patient's blood coagulation, comprising about 0.8 mg to about 1.5 mg apixaban or a pharmaceutically acceptable salt or solvate thereof.
  • a preparation for prevention wherein the preparation is administered to the patient twice or three times a day, the patient has atrial fibrillation, and the following criteria (1) to (3): Providing the formulation, which falls into at least two of them: Criteria (1) Age 80 and over; (2) Weight 60 kg or less; (3) Serum creatinine concentration of 1.5 mg / dl or more.
  • the present invention provides a blood trough of apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient, including apixaban or a pharmaceutically acceptable salt or solvate thereof, from about 50 ng / mL to about A pharmaceutical composition for maintaining 90 ng / mL, wherein about 0.8 mg to about 1.5 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof is administered to a patient twice a day
  • the pharmaceutical composition is provided such that it is used three times, the patient has atrial fibrillation, and meets at least two of the following criteria (1) to (3): Criteria (1) Age 80 and over; (2) Weight 60 kg or less; (3) Serum creatinine concentration of 1.5 mg / dl or more.
  • the present invention provides a method for inhibiting blood coagulation in a patient or treating or preventing a disease or disorder caused by blood coagulation, comprising about 0.8 mg to about 1.5 mg of apixaban or its Administering a pharmaceutically acceptable salt or solvate to the patient twice or three times a day, the patient having atrial fibrillation and the following criteria (1) to (3
  • the method is provided for at least two of the following: Criteria (1) Age 80 and over; (2) Weight 60 kg or less; (3) Serum creatinine concentration of 1.5 mg / dl or more.
  • blood coagulation can be inhibited or a disease or disorder caused by blood coagulation can be treated or prevented without reducing or causing adverse side effects such as bleeding and associated complications.
  • blood trough value has the general meaning known to those skilled in the art and refers to the lowest blood drug concentration at steady state upon repeated administration of the drug. In general, the blood concentration of a drug reaches its maximum concentration after absorption, and after reaching equilibrium, it decreases at a constant rate by metabolism and excretion over time.
  • maintain blood trough value means that the lowest blood drug concentration at steady state is within a specific value or range of specific values each time when the drug is administered repeatedly.
  • blood trough value is also referred to as trough value, trough concentration, blood trough concentration, or steady state minimum blood concentration.
  • blood peak value means the highest blood concentration after absorption of a drug.
  • the blood peak value exceeds the value expected for normal volume, the drug concentration is considered to be in the toxic range, and there is a risk of side effects and fatal complications. It is essential to control the dose so that the value is not in the addictive range beyond what would be expected with a normal dose.
  • the blood trough value and blood peak value can be measured by methods known to those skilled in the art.
  • the pharmacokinetics when the blood concentration transition has settled to a steady state by repeated administration, a strong correlation is observed between the blood trough value and the blood peak value. Predict blood peak value with trough value. This is because the time to reach the blood peak value may be affected by individual differences related to drug absorption. This is because the blood trough value is more reliable.
  • both the blood trough value and the blood peak value can be indicators of the occurrence of side effects.
  • the blood trough value can be an index of drug effect expression.
  • the blood is, for example, serum or plasma.
  • high-risk patient has non-valvular atrial fibrillation and is baseline (1) age 80 years or older; (2) body weight 60 kg or less; and (3) serum creatinine concentration of 1.5 mg / dl or more It means patients who fall into at least two of them.
  • pharmaceutically acceptable salt means a salt formed from a pharmaceutically acceptable non-toxic acid or base, including an inorganic acid or inorganic base, or an organic acid or organic base.
  • pharmaceutically acceptable salts include metal salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc, and lysine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, There are organic salts formed from diethanolamine, ethylenediamine, meglumine (N-methylglucamine) or procaine.
  • pharmaceutically acceptable salts include acid addition salts, base addition salts, ammonium salts, organic amine addition salts, and amino acid addition salts.
  • the acid addition salt include hydrochloride, hydrobromide, or hydroiodide.
  • solvate has a general meaning known to those skilled in the art and means a solvent-containing compound formed by the association of one or more solvent molecules to a compound.
  • Solvates include, for example, monosolvates, disolvates, trisolvates, and tetrasolvates.
  • Solvates include hydrates.
  • hydrate means a compound or salt thereof further comprising a stoichiometric or non-stoichiometric amount of water constrained by non-covalent intermolecular forces. Hydrates include, for example, monohydrate, dihydrate, trihydrate, tetrahydrate and the like.
  • treatment has a general meaning known to those skilled in the art and completely eliminates the disease or its symptoms or reduces the progression, severity and / or duration of the disease or its symptoms. Or it means remission.
  • prevention has a general meaning known to those skilled in the art and reduces or suppresses the risk of developing a disease or its symptoms, or one or more recurrences of a disease or its symptoms. It means to reduce or suppress.
  • the pharmaceutical composition of the present invention contains apixaban or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • Apixaban is one of the known oral anticoagulants targeting factor Xa and is a compound having the following structural formula (1): IUPAC name: 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide.
  • Apixaban is commercially available. Apixaban can also be produced by chemical synthesis.
  • the pharmaceutical composition of the present invention comprises apixaban or a pharmaceutically acceptable salt or solvate thereof, and is about 0.8 mg to about 1.5 mg, about 0.9 mg to about 1.5 mg, about 0.9 mg to about 1.4 mg per time. From about 1.0 mg to about 1.5 mg, from about 1.0 mg to about 1.4 mg, from about 1.0 mg to about 1.3 mg, from about 1.1 mg to about 1.3 mg, from about 1.2 mg to about 1.3 mg, or from about 1.25 mg Acceptable salts or solvates are used to be administered to patients twice or three times daily.
  • the pharmaceutical composition of the present invention is administered at a dose of about 1.0 mg to about 1.3 mg mg of apixaban or a pharmaceutically acceptable salt or solvate thereof to a patient twice or three times a day. It is used as follows. More preferably, the pharmaceutical composition of the present invention is used such that about 1.25 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof is administered to a patient twice a day. Preferably, administration is oral.
  • the pharmaceutical composition of the present invention containing apixaban or a pharmaceutically acceptable salt or solvate thereof can be formulated. Accordingly, the present invention also provides a preparation comprising apixaban or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the preparation of the present invention is preferably an oral preparation. Specific examples of the preparation include solid preparations such as tablets, pills, powders, powders, granules, or capsules, or sterile aqueous solutions, sterile non-aqueous solutions, suspensions, emulsions, There are liquid formulations such as syrups, emulsions or elixirs.
  • the preparation of the present invention contains a single dose of apixaban or a pharmaceutically acceptable salt or solvate thereof.
  • the dose per dose is about 0.8 to about 1.5 mg, about 0.9 to about 1.5 mg, about 0.9 to about 1.4 mg, about 1.0 to about 1.5 mg, about 1.0 to about 1.4 mg, about 1.0 to about 1.0 mg About 1.3 mg, about 1.1 mg to about 1.3 mg, about 1.2 mg to about 1.3 mg, or about 1.25 mg.
  • a single dose is from about 1.0 mg to about 1.3 mg. More preferably, a single dose is about 1.25 mg.
  • the formulation of the present invention may be a single formulation comprising a single dose of apixaban or a pharmaceutically acceptable salt or solvate thereof, or a single dose of apixaban or a pharmaceutically acceptable product thereof.
  • a plurality of preparations (for example, 2, 3, 4 or 5) containing the obtained salt or solvate separately may be used.
  • Each of the plurality of formulations comprises a single dose of apixaban or a pharmaceutically acceptable salt or solvate thereof in divided doses, the plurality of formulations totaling a single dose of apixaban Or a pharmaceutically acceptable salt or solvate thereof.
  • Each of the plurality of formulations may be the same or different.
  • each of the plurality of formulations is of the same shape and comprises the same divided dose of apixaban or a pharmaceutically acceptable salt or solvate thereof.
  • the preparation of the present invention is administered to patients twice or three times a day.
  • the formulations of the present invention are administered twice daily to the patient. More preferably, one or two doses of apixaban or a pharmaceutically acceptable salt or solvate thereof are administered to a patient two or three times a day.
  • the present invention provides a plurality of sets (eg, 2, 4, 6, 8, 10, 14) comprising one set of formulations comprising a single dose of apixaban or a pharmaceutically acceptable salt or solvate thereof. , Or 28 sets).
  • One set divides one formulation containing a single dose of apixaban or a pharmaceutically acceptable salt or solvate thereof, or a single dose of apixaban or a pharmaceutically acceptable salt or solvate thereof
  • a plurality of preparations One set is administered to the patient at a time. Two or three sets are administered to the patient per day.
  • the administration interval of the pharmaceutical composition or formulation of the present invention may be 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, or 22 hours. it can.
  • the pharmaceutical composition or formulation of the present invention is administered twice a day, the pharmaceutical composition or formulation of the present invention is administered in the morning (for example, before or after breakfast) and then in the afternoon (for example, before or after dinner) Can be administered.
  • the pharmaceutical composition or preparation of the present invention is basically supposed to be continuously administered, but the administration period of the pharmaceutical composition or preparation of the present invention is, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 12 months, Or more.
  • a drug holiday may be provided.
  • the drug holiday is provided, for example, when an open treatment is required.
  • the patient to whom the pharmaceutical composition or formulation of the present invention is administered has atrial fibrillation, for example, non-valvular atrial fibrillation, and falls under at least two of the following criteria (1) to (3) To: Criteria (1) Age 80 and over; (2) Weight 60 kg or less; (3) Serum creatinine concentration of 1.5 mg / dl or more.
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets the above criteria (1) and (2).
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and falls within criteria (1) and (3) above.
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets the above criteria (2) and (3).
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets all of the above criteria (1) to (3).
  • Patients who are administered the pharmaceutical composition or formulation of the present invention are less likely or not to cause harmful side effects such as bleeding and associated complications.
  • Patients to which the pharmaceutical composition or formulation of the present invention is administered are about 50 ng / mL to about 90 ng / mL, about 55 ng / mL to about 85 ng / mL, about 60 ng / mL to about 80 ng / mL Or about 75 ng / mL apixaban or a pharmaceutically acceptable salt or solvate thereof in blood.
  • the blood drug concentration is, for example, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, or about 12 hours after the administration, and becomes the blood trough value and is maintained until the next administration. .
  • the blood trough value is measured immediately before each administration, for example after taking 3 days or more.
  • the patient to which the pharmaceutical composition or formulation of the present invention is administered has a blood trough value of about 2 to about 4 times, about 2 to about 3.8 times, about 2 to about 3.6 times, about 2 to about 3.4 times.
  • the blood peak value may be doubled, about 2.2 times to about 3.2 times, about 2.4 times to about 3.0 times, about 2.6 times to about 2.8 times, or about 2.7 times.
  • the blood peak value is achieved, for example, from about 4 hours to about 10 hours, or from about 6 hours to about 8 hours after administration.
  • the patient's blood trough value and blood peak value can be constantly monitored using methods known to those skilled in the art, and the dosage and number of administrations can be changed according to the results.
  • the pharmaceutical composition or preparation of the present invention can be used for inhibiting blood coagulation in a patient. That is, the pharmaceutical composition or formulation of the present invention can be used as an anticoagulant. Moreover, the pharmaceutical composition or formulation of the present invention can be used for treating or preventing a disease or disorder caused by blood coagulation in a patient. Examples of diseases or disorders caused by blood coagulation include thrombosis, stroke (eg, ischemic stroke), embolism (eg, systemic embolism), cerebral infarction, and thromboembolism, eg, venous thromboembolism (Such as deep vein thrombosis and pulmonary thromboembolism).
  • the pharmaceutical composition or formulation of the invention is used to treat or prevent a patient's stroke (eg, ischemic stroke) or embolism (eg, systemic embolism).
  • a patient's stroke eg, ischemic stroke
  • embolism eg, systemic embolism
  • the pharmaceutical composition or formulation of the present invention can reduce or eliminate harmful side effects such as bleeding and associated complications.
  • the pharmaceutical composition or preparation of the present invention has a blood trough value of about 50 ng / mL to about 90 ng / mL, about 55 ng / mL to about 55 ng / mL for apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient. It can be used to maintain 85 ng / mL, about 60 ng / mL to about 80 ng / mL, or about 75 ng / mL.
  • the pharmaceutical composition or preparation of the present invention provides a blood peak value of apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient, and apixaban or a pharmaceutically acceptable salt or solvate thereof in the patient.
  • the pharmaceutical composition or formulation of the present invention has a blood trough value of about 50 ng / mL to about 90 ng / mL, about 55 / ng / mL of apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient.
  • the blood peak value is about 2 to about 4 times the blood trough value; About 2 times to about 3.8 times, about 2 times to about 3.6 times, about 2 times to about 3.4 times, about 2.2 times to about 3.2 times, about 2.4 times to about 3.0 times, about 2.6 times to about 2.8 times, or about Can be used to maintain 2.7 times.
  • the pharmaceutical composition or preparation of the present invention may contain one or more pharmaceutically acceptable carriers in addition to apixaban or a pharmaceutically acceptable salt or solvate thereof.
  • Pharmaceutically acceptable carriers are non-toxic, inert solid, semi-solid or liquid materials.
  • Pharmaceutically acceptable carriers include, for example, excipients, stabilizers, inert diluents, fillers, extenders, disintegrants, disintegration inhibitors, suspending agents, buffers, etc. known to those skilled in the art. Tonicity agents, chelating agents, pH adjusting agents, surfactants, encapsulating agents, binders, preservatives, antioxidants, lubricants, humectants, adsorbents, lubricants or any other formulation aids, etc. There is.
  • the pharmaceutically acceptable carrier can be appropriately selected depending on the kind of the preparation and the properties of the compound used.
  • pharmaceutically acceptable carriers include, but are not limited to, water, alcohols (such as ethanol), salt water (such as physiological saline), or a mixed solution thereof; inorganic salts such as sodium chloride; Metal salts or alkaline earth metal salts; monosaccharides such as glucose (dextrose), mannose, galactose, or fructose; sugar alcohols such as mannitol, inositol, or xylitol; disaccharides such as sucrose, lactulose, lactose, maltose, or trehalose Polysaccharides such as dextrin, dextran, cellulose, hyaluronic acid, or chondroitin sulfate; starches such as corn starch and potato starch; glycine, lysine, asparagine, arginine, glutamine, cysteine Amino acids such as aspartic acid or glutamic acid; tragacanth; gelatin; talc; coco
  • the amount of the pharmaceutically acceptable carrier is not particularly limited, and is determined by various factors such as the activity of the compound used and the type of preparation.
  • the content of the pharmaceutically acceptable carrier can be, for example, 1 to 99% by weight of the pharmaceutical composition or preparation of the present invention.
  • the pharmaceutical composition or formulation of the present invention can be used in combination with other active agents.
  • active agents include other anticoagulants such as dabigatran, rivaroxaban, edoxaban, or warfarin; neutralizing agents such as thrombin or prothrombin; procoagulants such as vitamin K or protamine; and tranexamic acid Or hemostatic agents such as ⁇ -aminocaproic acid.
  • the present invention provides a method of administering apixaban or a pharmaceutically acceptable salt or solvate thereof.
  • the method of administration of the present invention can reduce the possibility of adverse side effects such as bleeding and associated complications in a patient, or prevent such side effects from occurring.
  • the administration method of the present invention is about 0.8 mg to about 1.5 mg, about 0.9 mg to about 1.5 mg, about 0.9 mg to about 1.4 mg, about 1.0 mg to about 1.5 mg, about 1.0 mg to about 1.4 mg, About 1.0 mg to about 1.3 mg, about 1.1 mg to about 1.3 mg, about 1.2 mg to about 1.3 mg, or about 1.25 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof per day Including the step of administering 2 or 3 times.
  • the method of administration of the present invention comprises the step of administering about 1.0 mg to about 1.3 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof to a patient twice a day.
  • the administration method of the present invention comprises the step of administering about 1.25 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof to a patient twice a day.
  • administration is oral administration by tablets, pills, powders, powders, granules, capsules or the like.
  • the method of administration of the present invention comprises the step of administering to a patient a pharmaceutical composition or formulation of the present invention.
  • the administration interval can be 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, or 22 hours.
  • the pharmaceutical composition or preparation of the present invention is basically supposed to be continuously administered.
  • the administration period of the pharmaceutical composition or preparation of the present invention is, for example, 1 day, 2 days, 3 days. 4 days, 5 days, 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, It can be about 12 months or longer.
  • a drug holiday may be provided.
  • the drug holiday is provided, for example, when an open treatment is required.
  • the patient to whom apixaban or a pharmaceutically acceptable salt or solvate thereof is administered has atrial fibrillation, for example, non-valvular atrial fibrillation, and the following criteria (1) Applicable to at least two of (3): Criteria (1) Age 80 and over; (2) Weight 60 kg or less; (3) Serum creatinine concentration of 1.5 mg / dl or more.
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets the above criteria (1) and (2).
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and falls within criteria (1) and (3) above.
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets the above criteria (2) and (3).
  • the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets all of the above criteria (1) to (3).
  • the patient after administration is about 50 ng / mL to about 90 ng / mL, about 55 ng / mL to about 85 ng / mL, about 60 ng / mL to about 80 ng / mL, or about 75 ng / mL.
  • the blood trough value of mL of apixaban or a pharmaceutically acceptable salt or solvate thereof may be indicated.
  • the blood drug concentration is, for example, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, or about 12 hours after the administration, and becomes the blood trough value and is maintained until the next administration. .
  • the blood trough value is measured immediately before each administration, for example after taking 3 days or more.
  • the patient's blood trough is about 2 to about 4 times, about 2 to about 3.8 times, about 2 to about 3.6 times, about 2 to about 3.4 times, about 2.2 to about 3.2 times About 2.4 times to about 3.0 times, about 2.6 times to about 2.8 times, or about 2.7 times blood peak values.
  • the blood peak value is achieved, for example, from about 4 hours to about 10 hours, or from about 6 hours to about 8 hours after administration.
  • the patient's blood trough value and blood peak value can be constantly monitored using methods known to those skilled in the art, and the dosage and number of administrations can be changed according to the results.
  • the patient's blood coagulation can be inhibited using the administration method of the present invention.
  • the administration method of the present invention can be used to treat or prevent a disease or disorder caused by blood coagulation in a patient.
  • diseases caused by blood coagulation include thrombosis, stroke (eg, ischemic stroke), embolism (eg, systemic embolism), cerebral infarction, and thromboembolism, eg, venous thromboembolism (deep) Venous thrombosis and pulmonary thromboembolism).
  • the administration methods of the present invention can be used to treat or prevent a patient's stroke (eg, ischemic stroke) or embolism (eg, systemic embolism).
  • the method of administration of the present invention provides a blood trough of apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient of about 50 ng / mL to about 90 ng / mL, about 55 ng / mL to about 85 ng / ml. It can be used to maintain mL, about 60 ng / mL to about 80 ng / mL, or about 75 ng / mL. Further, the administration method of the present invention provides the blood peak value of apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient, and the blood peak value of apixaban or a pharmaceutically acceptable salt or solvate thereof in the patient.
  • the method of administration of the present invention provides a blood trough value of apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient of about 50 ng / mL to about 90 ng / mL, about 55 ng / mL to about 85 ng / mL, about 60 ng / mL to about 80 ng / mL, or about 75 ng / mL, and the blood peak value of apixaban or a pharmaceutically acceptable salt or solvate thereof in the patient About 2 times to about 4 times, about 2 times to about 3.8 times, about 2 times to about 3.6 times, about 2 times to about 3.4 times, about 2.2 times to about 3.2 times, about 2.4 times to about the blood trough value It can be used to maintain about 3.0 times, about 2.6 times to about 2.8 times, or about 2.7 times.
  • the administration method of the present invention can be combined with administration of other active agents.
  • other active agents include other anticoagulants such as dabigatran, rivaroxaban, edoxaban, or warfarin; neutralizing agents such as thrombin or prothrombin; procoagulants such as vitamin K or protamine; and tranexamic acid Or hemostatic agents such as ⁇ -aminocaproic acid.
  • Example 1 Comparison of blood trough levels between healthy and high-risk groups
  • the blood trough and blood peak values are as follows: Heading: 10 mg twice a day, blood trough: approx. 130 ng / mL, blood peak: approx. 350 ng / mL 5 mg twice a day, blood trough: approx. 75 ng / mL, blood peak: approx. 200 ng / mL 2.5 mg twice a day, blood trough: approx. 30 ng / mL, blood peak: approx. 80 ng / mL.
  • Non-patent Document 1 a blood trough value of about 75 ng / mL may be within a therapeutically effective range. I understood. Even in the high-risk group, it is considered important to maintain a blood trough level of about 75 ng / mL.
  • Example 2 Results of administering low-dose apixaban to high-risk group
  • a high-risk group was administered 1.25 mg of apixaban twice a day, and the blood trough level was confirmed to be the recommended value.
  • a high-risk group (74 years old, male, body weight 55 kg, creatinine 1.6 mg / dL) was administered 2.5 mg apixaban twice a day for 2 weeks, resulting in a blood trough of 116 ng / mL
  • the blood trough level was 63 ng / mL.
  • the onset of ischemic stroke and systemic embolism was not confirmed. Further, side effects such as bleeding and accompanying complications were not confirmed in the patient.

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Abstract

Cette composition pharmaceutique est caractérisée en ce qu'elle contient de l'apixaban et en ce qu'elle est utilisée de manière telle qu'environ 0,8 mg à environ 1,5 mg d'apixaban ou d'un sel pharmacologiquement acceptable correspondant ou d'un solvate correspondant, par exemple, est administré à un patient deux fois ou trois fois par jour. Le patient présente une fibrillation auriculaire et satisfait au moins à deux des critères suivants (1)-(3) : (1) âge de 80 ans ou plus ; (2) poids de 60 kg ou moins ; (3) concentration en créatinine sérique de 1,5 mg/dl ou plus.
PCT/JP2019/019479 2018-05-21 2019-05-16 Composition pharmaceutique contenant de l'apixaban à faible dose WO2019225467A1 (fr)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"2. 1 Recommended Dose", ELIQUIES (APIXABAN) LABEL, 2016, pages 1 - 44 *
BARRA, M. E. ET AL.: "Evaluation of Dose-Reduced Direct Oral Anticoagulant Therapy", THE AMERICAN JOURNAL OF MEDICINE, vol. 129, no. 11, 2016, pages 1198 - 1204, XP029780237, ISSN: 0002-9343, DOI: 10.1016/j.amjmed.2016.05.041 *

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