WO2019225467A1

WO2019225467A1 - Pharmaceutical composition containing low-dose apixaban

Info

Publication number: WO2019225467A1
Application number: PCT/JP2019/019479
Authority: WO
Inventors: 原　正彦
Original assignee: 株式会社ＲｅｓｅａｒｃｈＭｉｎｄ
Priority date: 2018-05-21
Filing date: 2019-05-16
Publication date: 2019-11-28
Also published as: JP6562368B1; JP2019202942A

Abstract

This pharmaceutical composition is characterized by containing apixaban and by being used so that approximately 0.8 mg to approximately 1.5 mg of apixaban or a pharmacologically acceptable salt thereof or a solvate thereof per instance is administered to a patient twice or three times per day. The patient has atrial fibrillation and meets at least two of the following criteria (1)-(3): (1) age 80 years or more; (2) weight 60 kg or less; (3) serum creatinine concentration 1.5 mg/dL or higher.

Description

Pharmaceutical composition comprising a low dose of apixaban

The present invention relates to a pharmaceutical composition containing a low dose of apixaban and a method for administering apixaban. In particular, 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. At present, 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.

It is known that administration of a high dose of apixaban causes harmful side effects such as bleeding and associated complications. In Japan, there is still no appropriate neutralizer for apixaban. Currently, in order to suppress the onset of ischemic stroke and systemic embolism in patients with nonvalvular atrial cells, the administration of 5.0 mg of apixaban twice a day is recommended for adult men (Non-patent Document 1). And 2). On the other hand, patients with non-valvular atrial cells who meet at least two of criteria (1) age 80 years or older; (2) body weight 60 kg or less; and (3) serum creatinine concentration 1.5 mg / dl or more (this In the specification, “high-risk group”) has a high risk of bleeding, and therefore 2.5 mg of apixaban is recommended to be administered twice a day (Non-patent Document 1). Higher doses are more likely to cause adverse side effects, and lower doses have no therapeutic effect.

Here, we discovered that there is a group of patients whose blood levels are unexpectedly high. Even in such a patient group, a new administration method of apixaban that does not cause harmful side effects is required.

Japanese Patent No. 4249621 Special table 2013-521226 gazette

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.

In order to solve the above problem, the present inventor has focused on the blood trough value of apixaban. When comparing the blood trough value of apixaban in healthy people and high risk group, 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. In addition, in 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.

Accordingly, 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. Wherein about 0.8 mg to about 1.5 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof is used to be administered to the patient twice or three times a day, Provided is 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.

Further, 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 Alternatively, 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.

Furthermore, 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.

For patients with atrial fibrillation and who meet at least two of the criteria (1) age 80 years and older; (2) body weight 60 kg or less; and (3) serum creatinine concentration 1.5 mg / dl or more In addition, 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.

These are plasma concentration transitions and pharmacokinetic parameters when 2.5, 5, and 10 mg of apixaban were administered twice daily to healthy adult males (n = 6).

(1. Definition)
The term “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. The term “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. The term “blood trough value” is also referred to as trough value, trough concentration, blood trough concentration, or steady state minimum blood concentration.
The term “blood peak value” means the highest blood concentration after absorption of a drug. If 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. In addition, as 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.
Therefore, both the blood trough value and the blood peak value can be indicators of the occurrence of side effects. In addition, when it is necessary to maintain a blood concentration of a certain level or more for the drug effect expression, the blood trough value can be an index of drug effect expression. The blood is, for example, serum or plasma.

The term “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.

The term “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. Examples of 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. Examples of pharmaceutically acceptable salts include acid addition salts, base addition salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Examples of the acid addition salt include hydrochloride, hydrobromide, or hydroiodide.

The term “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. The term “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.

The term “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.
The term “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 term “about” refers to a range acceptable to those skilled in the art, for example, 0.1 to 10%, 0.1 to 5%, 0.1 to 1.0%, or 0.1 to 0.5%.

(2. Pharmaceutical composition of the present invention)
The pharmaceutical composition of the present invention contains apixaban or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. By using the pharmaceutical composition of the present invention, the potential for adverse side effects such as bleeding and associated complications in patients can be reduced or no such side effects can occur.

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. Preferably, 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. Preferably, 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. Preferably, 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. Preferably, 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.

Furthermore, 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. For example, when 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. During the administration period, 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.

In one embodiment, the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets the above criteria (1) and (2). In another embodiment, the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and falls within criteria (1) and (3) above. In yet another embodiment, the patient is a patient who has atrial fibrillation, for example, non-valvular atrial fibrillation, and meets the above criteria (2) and (3). In yet another embodiment, 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). Preferably, 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). 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. In addition, 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. 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 It can be used to maintain about 3.0 times, about 2.6 times to about 2.8 times, or about 2.7 times. Preferably, 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. 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 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.

Specific examples of 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; cocoa butter or wax; wax or beeswax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, or hardened oil Esters such as ethyl oleate or ethyl laurate; agar; hydroxide such as sodium hydroxide; alginic acid; isotonic salt solution; Ringer's solution; buffer such as phosphate buffer; Further specific examples of pharmaceutically acceptable carriers include anhydrous lactose, crystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate, hypromellose, lactose hydrate, titanium oxide, triacetin, and yellow There is iron sesquioxide.

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. Examples of 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 ε-aminocaproic acid.

(3. Administration method of the present invention)
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. Preferably, 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. More preferably, 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. Preferably, administration is oral administration by tablets, pills, powders, powders, granules, capsules or the like. In one embodiment, 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. However, 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. During the administration period, a drug holiday may be provided. The drug holiday is provided, for example, when an open treatment is required.

In the administration method of the present invention, 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.

Patients after administration are unlikely or unlikely to have adverse side effects such as bleeding and associated complications. Preferably, 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.

After administration, 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 coagulation can be inhibited using the administration method of the present invention. Moreover, 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. Examples of 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). Preferably, 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). By using the administration method of the present invention, harmful side effects such as bleeding and associated complications can be reduced or eliminated.

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. 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 3.0 times the trough value , About 2.6 times to about 2.8 times, or about 2.7 times. Preferably, 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. Examples of 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 ε-aminocaproic acid.

(4. Example)
Examples of the present invention will be described below. The following examples are set forth to enhance the understanding of the claims of the present invention and are not intended to limit the scope of the claims of the present invention.

Example 1
(Comparison of blood trough levels between healthy and high-risk groups)
Data already published include changes in plasma concentrations and pharmacokinetic parameters when healthy adult males (n = 6) were administered 2.5, 5, and 10 mg of apixaban twice daily (Figure 1, non- (See page 63 of Patent Document 1). From this data, in healthy adults, the drug concentration is almost steady on the third day, and from the values on the third to seventh days, 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.

It was also found that the blood trough value almost doubled when the dose was doubled, and the blood peak value showed about 2.7 times the blood trough value. In patients with valvular atrial fibrillation, 2 doses of 5 mg are recommended (Non-patent Document 1), and therefore, 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.

Based on the above consideration, the blood trough value of the high risk group was measured. High-risk group (n = 6), 2.5 mg of apixaban was administered twice a day (once in the morning and in the afternoon) for at least 2 weeks, and in the morning when the drug concentration reached a steady state Blood was collected immediately before and the trough level in blood was measured. The results are shown in Table 1 below.

It was confirmed that there were cases (2 patients) whose trough value of blood concentration exceeded 200 ng / mL. This is so high that it exceeds the peak of 5 mg 男性 2 doses for adult men. The majority (4 patients) had trough levels in blood exceeding 150 ng / mL. This was twice as high as 75 ng / mL, which is the trough value for adult males administered twice at 5 mg5. In the high-risk group, even when 2.5 mg of apixaban was administered twice a day, it was completely unpredictable that the blood trough level showed such an abnormally high level.

(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 However, when 1.25 mg of apixaban was administered to the patient twice a day for 2 weeks, the blood trough level was 63 ng / mL. In the patient, 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.

Claims

A pharmaceutical composition containing apixaban or a pharmaceutically acceptable salt or solvate thereof for inhibiting blood coagulation in a patient, or for treating or preventing a disease or disorder caused by blood coagulation, About 0.8 mg to about 1.5 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof is used to be administered to the patient twice or three times a day, and the patient has atrial fibrillation And the pharmaceutical composition corresponding to 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 pharmaceutical composition according to claim 1, wherein about 1.25 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof is used twice a day for a patient.
The pharmaceutical composition according to claim 1 or 2, wherein the patient exhibits a blood trough value of about 50 ng / mL to about 90 ng / mL of apixaban or a pharmaceutically acceptable salt or solvate thereof after administration. .
The pharmaceutical composition according to claim 3, wherein the patient further exhibits a blood peak value of about 2 to about 4 times the blood trough value.
The pharmaceutical composition according to any one of claims 1 to 4, wherein the disease or disorder caused by blood coagulation is stroke or embolism.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the disease or disorder caused by blood coagulation is ischemic stroke or systemic embolism.
The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient has non-valvular atrial fibrillation.
The pharmaceutical composition according to any one of claims 1 to 7, wherein the administration is oral administration.
A preparation containing about 0.8 mg to about 1.5 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof for inhibiting blood coagulation in a patient or treating or preventing a disease or disorder caused by blood coagulation. The preparation is administered to the patient twice or three times a day, the patient has atrial fibrillation, and at least two or more of the following criteria (1) to (3) Applicable to the formulation:
Criteria (1) Age 80 and over;
(2) Weight 60 kg or less;
(3) Serum creatinine concentration of 1.5 mg / dl or more.
10. The preparation according to claim 9, wherein about 1.25 mg of apixaban or a pharmaceutically acceptable salt or solvate thereof is used to be administered to a patient twice a day.
The preparation according to claim 9 or 10, wherein the patient after administration exhibits a blood trough value of about 50 ng / mL to about 90 ng / mL of apixaban or a pharmaceutically acceptable salt or solvate thereof.
The preparation according to claim 11, wherein the patient further exhibits a blood peak value of about 2 to about 4 times the blood trough value.
The preparation according to any one of claims 9 to 12, wherein the disease or disorder caused by blood coagulation is stroke or embolism.
The preparation according to any one of claims 9 to 13, wherein the disease or disorder caused by blood coagulation is ischemic stroke or systemic embolism.
The preparation according to any one of claims 9 to 14, wherein the patient has non-valvular atrial fibrillation.
The preparation according to any one of claims 9 to 15, wherein the administration is oral administration.
Maintaining the blood trough value of apixaban or a pharmaceutically acceptable salt or solvate thereof in a patient, including apixaban or a pharmaceutically acceptable salt or solvate thereof, between about 50 ng / mL and about 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 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.
18. The pharmaceutical composition according to claim 17, for maintaining the blood peak value in the patient at about 2 to about 4 times the blood trough value.