JP6168579B1 - Platelet production promoter containing Rustrombopag for patients with severe liver dysfunction - Google Patents

Abstract

[PROBLEMS] To achieve a sufficient platelet count increase effect for a patient with severe liver dysfunction (Child-Pugh classification C) and to not increase the platelet count excessively. Another object is to provide a platelet production promoter containing a pharmaceutically acceptable salt thereof. The present inventor has found that rustrombopag or a pharmaceutically acceptable salt thereof is useful as a platelet production promoter for patients with severe liver dysfunction (Child-Pugh classification C). . A platelet production promoter containing rustthrombopag or a pharmaceutically acceptable salt thereof for patients with severe liver dysfunction (Child-Pugh classification C) has been found. [Selection figure] None

Description

  The present invention relates to a platelet production promoter containing rusthrombopag for patients with severe liver dysfunction.

  Thrombocytopenia is a disease that causes a tendency to bleed due to decreased platelets due to increased platelet destruction and insufficient platelet production. Bleeding symptoms include cerebral hemorrhage, internal bleeding, punctate bleeding, purpura, mucosal bleeding (nasal bleeding, gastrointestinal bleeding, genital bleeding), etc. Excessive bleeding may be seen after surgery.

Chronic liver disease is known as one of the causes of thrombocytopenia. In patients with chronic liver disease, a decrease in the number of platelets is observed with a decrease in liver reserve capacity and an increase in spleen function due to the progression of the stage. Many of the causes of chronic hepatitis are hepatitis B or C infection, and hepatitis C is the most common. Hepatitis C tends to become chronic and progresses to cirrhosis and further to hepatocellular carcinoma, and about 34,000 people die annually. In patients with thrombocytopenia when hepatitis or liver cancer is treated, splenectomy and partial splenic artery embolization (when antiviral therapy using interferon is not available, or when performing invasive procedures such as laparotomy and local therapy) PSE) or platelet transfusion may be required.
However, splenectomy is highly invasive and has been reported to cause portal thrombosis and decreased immunity, PSE has been reported to cause splenic abscesses and sepsis, and platelet transfusion has side effects associated with transfusion (transfusion) There are problems such as risk of related acute lung injury and infection) and the expiration date of the platelet preparation itself is short (4 days after blood collection), which is not necessarily a safe and simple treatment. It is also known that when platelets are transfused, repeated transfusions may promote antibody production and cause platelet transfusion refractory.
Under such circumstances, a therapeutic drug for thrombocytopenia that has no side effects and can be easily administered is desired.

  Thrombopoietin (TPO) is a cytokine that acts on hematopoietic stem cells and megakaryocyte progenitor cells, promotes proliferation and differentiation into megakaryocytes, and acts on platelet hematopoiesis. In the past, clinical trials of genetically modified human TPO were conducted, but neutralizing antibodies against endogenous TPO were induced, and development was discontinued due to antigenic problems. Among cytokines acting on megakaryocyte hematopoiesis, the only injection of interleukin 11 is clinically applied in the United States, but there are side effects such as fluid retention, increased heart rate, and edema, so platelets due to bone marrow suppression after chemotherapy It is approved only for the purpose of improving the reduction.

Under such circumstances, a compound having a thrombopoietin receptor agonist activity is expected as a therapeutic agent for various thrombocytopenia that can replace existing therapeutic methods including platelet transfusion and treatment. Currently, as a therapeutic agent for “thrombocytopenia in patients with chronic liver disease who are scheduled for a long-awaited open procedure”, thrombopogceptor, which is a thrombopoietin receptor agonist (Patent Document 1, Patent Document 2), is being used in Japan. Approved and sold.
In the package insert (Non-patent Document 1) of 3 mg of Mulpleta (registered trademark) containing Rustrombopag as an active ingredient, the column “Precautions for use related to dosage and administration” has a “platelet count of 50,000 When the dose is increased to 20,000 / μL or more before the start of administration of this drug, appropriate treatment such as discontinuation of this drug should be taken ”. In the “Pharmacokinetics” column of the document, there are 8 cases of “healthy adults, mild (Child-Pugh classification A) and moderate (Child-Pugh classification B) liver dysfunction” to 0.75mg when a (non-approved dose) was a single oral administration, C _max and AUC of mild hepatic dysfunction, C _max of moderate hepatic dysfunction who are healthy adult comparable, moderate hepatic dysfunction AUC was about 20% higher than healthy adults. "
Also, in the same document, patients with severe liver dysfunction (Child-Pugh classification C) should not be contraindicated, that is, do not administer rusthrombopag because blood levels may increase. It is supposed to be.

Japanese Patent No. 4106066 Patent No. 5164181

Brand name: Mulpreta Tablets (3 mg, 25 mg): (General name: lusutrombopag) package insert (1st edition, September 2015), Shionogi & Co., Ltd.

Rustrombopag tablets have been approved for thrombocytopenia in patients with chronic liver disease who are scheduled for elective open surgery. However, it is contraindicated in patients with severe liver dysfunction (Child-Pugh classification C), and administration is prohibited.
Therefore, an object of the present invention is to obtain both a sufficient platelet count increase effect even in patients with severe liver dysfunction (Child-Pugh classification C) and not to increase the platelet count excessively. An object of the present invention is to provide a platelet production promoter containing lustrombopag or a pharmaceutically acceptable salt thereof.

  The present inventor has found that rustthrombopag or a pharmaceutically acceptable salt thereof is useful as a platelet production promoter for patients with severe liver dysfunction (Child-Pugh classification C). A platelet production promoter containing rustthrombopag or a pharmaceutically acceptable salt thereof for patients with severe liver dysfunction (Child-Pugh classification C) has been found.

That is, the present invention relates to the following.
[1] A platelet production promoter containing rusthrombopag or a pharmaceutically acceptable salt thereof, which is administered to a patient with severe liver dysfunction.
[2] A platelet production promoter containing Rustrombopag or a pharmaceutically acceptable salt thereof, which is administered to adults including patients with severe liver dysfunction.
[3] The platelet production promoter according to the above [2], wherein the adult including a patient with severe liver dysfunction is a chronic liver disease patient who is scheduled for a waiting-time open procedure.
[4] The platelet production promoter according to [2] above, wherein the adults including patients with severe liver dysfunction are thrombocytopenic patients.
[5] The platelet production promoter according to any one of [1] to [4], wherein the severe liver dysfunction is a liver dysfunction classified as Child-Pugh class C.

  The platelet production promoter containing Rustrombopag or a pharmaceutically acceptable salt thereof according to the present invention is useful in that it can be used for patients with severe liver dysfunction (Child-Pugh classification C). .

FIG. 1 is a graph plotting whole body clearance (CL / F) when ruthrombopag was administered to patients with each Child-Pugh score. The horizontal axis is Child-Pugh score, and the vertical axis is whole body clearance (CL / F). FIG. 2 is a graph showing changes in plasma concentration of rusthrombopag when rusthrombopag was administered to patients of each Child-Pugh classification. The horizontal axis is the time after administration, and the vertical axis is the concentration (ng / mL) of ruthrombopag in plasma.

  The meaning of each term used in this specification will be described below. Unless otherwise noted, each term is used in the same meaning whether used alone or in combination with other terms.

  Ruthrombopag is a low molecular weight human thrombopoietin receptor agonist, and its chemical formula is “(E) -3- [2,6-Dichloro-4- [4- [3-[(S) -1-hexyloxyethyl] ] -2-methoxyphenyl] -thiazol-2-ylcarbamoyl] -phenyl] -2-methylacrylic acid ”. Ruthrombopag is represented by the following chemical structure.

  Pharmaceutically acceptable salts include, for example, rust thrombopag, alkali metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc) , Iron, etc.), ammonia, organic bases (for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (Eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, Oxalic acid, maleic acid, fumaric acid, Nderu acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

  Ruthrombopag or a pharmaceutically acceptable salt thereof may form solvates (eg, hydrates, etc.), co-crystals and / or crystal polymorphs, and the present invention provides such various solvates. Products, co-crystals and polymorphs are also included. The “solvate” may be coordinated with Ruthrombopag with any number of solvent molecules (for example, water molecules). By leaving leuthrombopag or a pharmaceutically acceptable salt thereof in the air, moisture may be absorbed and adsorbed water may adhere or a hydrate may be formed. In addition, crystal polymorphs may be formed by recrystallizing ruthrombopag or a pharmaceutically acceptable salt thereof. “Co-crystal” means that the thrombopag or salt and counter molecule are present in the same crystal lattice and may contain any number of counter molecules.

  Ruthrombopag or a pharmaceutically acceptable salt thereof can be converted into a prodrug by chemically modifying the carboxyl group of ruthrombopag. Ruthrombopag or a pharmaceutically acceptable salt thereof used in the present invention also includes such prodrugs. A prodrug is a derivative of rusthrombopag having a chemically or metabolically degradable group, which is a compound that becomes pharmaceutically active rusthrombopag in vivo upon solvolysis or under physiological conditions. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo and converted to rusthrombopag, compounds that are hydrolyzed by gastric acid, etc., and converted to rusthrombopag, etc. Include. Methods for selecting and producing suitable prodrug derivatives are described, for example, in “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.

  The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.

  Thrombocytopenia means a state in which the number of platelets has decreased, and a thrombocytopenic patient means a patient with thrombocytopenia. For example, patients having a platelet count of less than 50,000 / μL can be mentioned.

  In general, the Child-Pugh classification is used to evaluate the degree of liver damage. The points of each item in Table 1 are added and classified by the total points. A total of 5 to 6 points is Class A, a total of 7 to 9 points is Class B, and a total of 10 to 15 points is Class C.

  Child-Pugh classification C refers to a classification belonging to severe liver dysfunction among liver dysfunctions.

  Patients with severe liver dysfunction are those who belong to Child-Pugh classification C. Such patients include patients with chronic liver disease and patients with thrombocytopenia who are scheduled for elective open surgery.

  Open surgery means an invasive procedure involving bleeding.

  A waiting-type open blood procedure is to perform an open blood procedure while waiting for a timing suitable for treatment during the course of a medical condition. Waiting invasive procedures include various invasive open therapies, particularly various minimally invasive open therapies. For example, percutaneous radiofrequency ablation (RFA), percutaneous microwave coagulation (MCT), percutaneous ethanol injection therapy (PEIT), hepatic artery embolization (TAE), hepatic artery arterial infusion chemotherapy (Lip -TAI), hepatic artery chemoembolization (TACE), ultrasonic endoscopic guided puncture aspiration (EUS-FNA), laparoscopic radiofrequency ablation (LRA), laparoscopic microwave coagulation (LMC) , Endoscopic metallic stent insertion (EMS), Endoscopic papillary sphincterotomy (EST), Endoscopic papillary balloon dilatation (EPBD), Ultrasound endoscopic guided puncture aspiration (EUS- FNA), endoscopic polypectomy, endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR), percutaneous endoscopic gastrostomy (PEG), Endoscopic varicose vein ligation (EVL), ultrasound endoscopic guided puncture (EUS-FNA), transurethral bladder tumor resection (TURBT), transurethral ureteral lithotripsy (TU) L), percutaneous needle biopsy, laparoscopic biopsy, ultrasound-guided biopsy, laparoscopy, arthroscopic surgery, endoscopy scheduled for tissue biopsy, argon plasma coagulation therapy (APC) ), Various punctures, tooth extraction, and the like.

  Chronic liver disease is a disease in which hepatocytes are destroyed by inflammation that persists for a long period of time, and gradually progresses to cirrhosis, sometimes causing liver cancer. Chronic liver disease includes chronic liver disease due to hepatitis B virus, chronic liver disease due to hepatitis C virus, alcoholic chronic liver disease, and non-alcoholic fatty chronic liver disease (NASH). In Japan, about 70% of chronic hepatitis is caused by hepatitis C and about 20% is caused by hepatitis B.

  Rust thrombopag or a pharmaceutically acceptable salt thereof can be produced, for example, by the production methods described in Patent Document 1 and Patent Document 2. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. As Rustrombopag, 3 mg of commercially available Mulpreta (registered trademark) tablets can also be used.

  Rustrombopag or a pharmaceutically acceptable salt thereof can be administered either orally or parenterally. Examples of parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.

  In the case of oral administration, solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.) and liquids for internal use (eg, suspensions, emulsions, elixirs, syrups) Preparations, limonade agents, spirits, fragrances, extracts, decoctions, tinctures, etc.), etc. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and the powders and granules are dry syrups. Alternatively, the capsule may be a soft capsule, a microcapsule or a sustained release capsule.

  In the case of parenteral administration, injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas, Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered. The injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.

  Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form are mixed with an effective amount of rusthrombopag or a pharmaceutically acceptable salt thereof as necessary to produce a pharmaceutical product. It can be a composition. Furthermore, the pharmaceutical composition can be used for pediatric, elderly, and severely ill patients by appropriately changing the effective amount, dosage form and / or various pharmaceutical additives of lusthrombopag or a pharmaceutically acceptable salt thereof. Or it can also be set as the pharmaceutical composition for surgery. The pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. In addition, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old. The elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.

  The dose of rusthrombopag or a pharmaceutically acceptable salt thereof is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc. 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 Influence of Child-Pugh score and Child-Pugh classification on systemic clearance (CL / F) of Rustrombopag To investigate the effect of Rustrombopag on patients with severe liver dysfunction, Based on the plasma concentration data of 149 patients treated with rustthrombopag in Japanese clinical trials (M0623, M0625, M0626, and M0631) conducted for patients with liver disease, a new empirical Bayesian method using a population pharmacokinetic model was used. Individual apparent total body clearance (CL / F) of the patient was estimated and the effect of the Child-Pugh score and Child-Pugh classification on Rust thrombopag was examined. Rust thrombopag used the formulation described in Japanese Patent No. 5557146.
Here, the “experience Bayesian method using a population pharmacokinetic model” is a method for estimating CL / F values from population mean values and variances of parameters and patient plasma drug concentration data on the population model. Say.
The “apparent whole body clearance (CL / F)” is CL / F (L / hr), and was calculated by a post-hoc analysis by an empirical Bayesian method using a population pharmacokinetic model.

The outline of each domestic clinical trial is as follows.
M0623 for thrombopag 0.25 mg, 0.5 mg, 1 mg, 1.5 mg, or 2 mg per day for patients with thrombocytopenia due to chronic liver disease who is not Child-Pugh class C who is scheduled for percutaneous liver cancer ablation This is a clinical study aimed at confirming the efficacy, safety and pharmacokinetics of repeated oral administration once a day for 7 days, and searching for the optimal dose of Rustrombopag.
M0625 is intended for patients with thrombocytopenia due to chronic liver disease who is not Child-Pugh class C who is scheduled for percutaneous liver cancer ablation, rusthrombopag 2.5 mg, 3 mg, 3.5 mg, or 4 mg once a day7 This is a clinical study aimed at confirming the efficacy, safety and pharmacokinetics of repeated oral administration on a daily basis.
M0626 is orally administered rusthrombopag 2mg, 3mg, or 4mg once a day for 7 days in patients with thrombocytopenia due to chronic liver disease that is not Child-Pugh classification C and is scheduled for percutaneous liver cancer cauterization Efficacy, safety and pharmacokinetics at the time of treatment, avoidance of platelet transfusion before percutaneous liver cancer ablation This is a clinical trial aimed at examining the rate as an index.
M0631 is the efficacy of oral administration of rusthrombopag 3mg once a day for 7 days in patients with thrombocytopenia due to chronic liver disease who is not Child-Pugh class C who is scheduled for open invasive surgery. To confirm safety and pharmacokinetics, and to verify the superiority of placebo when administered with Rastrombopag 3 mg as a pretreatment for open invasive surgery, using the rate of avoidance of platelet transfusion before open invasive surgery as an index It is a clinical trial aiming at that.
M0633 is rusthrombopag 3 mg given once a day for 7 days in patients who have not been treated with rusthrombopag in an open-label study in patients with thrombocytopenia due to chronic liver disease of Child-Pugh class A or B To confirm the safety, pharmacokinetics, and efficacy of ruustrombopag when administered as a pre-invasive procedure, and for patients with previous experience with ruthrombopag This is a clinical study aimed at confirming safety, pharmacokinetics and efficacy when administered.
M0634 is the efficacy of repeated oral administration of rusthrombopag 3mg once a day for 7 days in patients with thrombocytopenia due to chronic liver disease that is not Child-Pugh class C and is scheduled for open invasive surgery. This is a clinical study in foreign countries aimed at confirming safety and pharmacokinetics.

As a result, as shown in FIG. 1, there was no CL / F variation according to the Child-Pugh score, and no significant difference was observed between the Child-Pugh score and the Child-Pugh classification. Even in patients with Child-Pugh classification C exceeding 1, the possibility of unexpected variation was considered to be low.
Based on these results, the present inventors have found that Rustrombopag or a pharmaceutically acceptable salt thereof is useful as a platelet production promoter for patients with severe liver dysfunction (Child-Pugh classification C). I found it. That is, the present inventors have found a platelet production promoter containing rusthrombopag or a pharmaceutically acceptable salt thereof for patients with severe liver dysfunction (Child-Pugh classification C).

Example 2
To confirm the changes in safety, pharmacokinetics, and platelet count of patients with thrombocytopenia due to Child-Pugh Class C chronic liver disease, platelets due to Child-Pugh Class C chronic liver disease In 15 patients with reduction, 3 mg of rusthrombopag is administered once a day for 7 days. Lustrombopag uses 3 mg of Mulpleta (registered trademark) tablets.

(Subject selection criteria)
For those who meet all the following selection criteria.
1) Male or female patient over 20 years old at the time of consent 2) Patient with thrombocytopenia due to chronic liver disease of Child-Pugh class C 3) Patient with platelet count less than 50,000 / μL at screening 4) Examination at screening , Patients whose liver damage falls under Child-Pugh classification C 5) Patients whose Eastern Cooperative Oncology Group (ECOG) has a performance status of Grade 0 or 1

ECOG Performance Status is shown in Table 2 below.

(Dose and administration method)
One 3 mg tablet of Rustrombopag is orally administered once a day. The study drug will be administered for 7 days. The administration on the second day should be at least 12 hours after the administration on the first day, and administration of the investigational drug on and after the second day should be performed at the same time as much as possible.
The clinical examination (platelet count) on the 3rd to 7th days is performed before the administration of the study drug on that day, and the study drug is administered after confirming that the platelet count measured on the day does not meet the criteria for discontinuation of administration (described later) To do.

(Discontinuation criteria)
The investigator (shareholder) will discontinue study drug administration if subjects meet the criteria below.
・ If the platelet count increases by 20,000 / μL or more compared to before administration and reaches 50,000 / μL or more ・ If an adverse event related to blood clot occurs ・ Severe or unacceptable adverse event If the study investigator decides that the investigator should be discontinued. ・ If the investigator decides that the study investigator should discontinue because the study drug effect is insufficient. When it becomes clear that the subject is inappropriate for this study ・ When the subject cannot be tracked ・ For any other reason, the investigator determines that the subject should be discontinued

(Test Example 1) Evaluation of changes in platelet count
Blood samples will be collected before and after the administration of Lusthrombopag to patients with Child-Pugh classification C, and the platelet count, immature platelet ratio, and reticulated platelet ratio will be examined as hematological tests.

The following items are analyzed for changes in platelet count.
(1) Transition of platelet count ・ A summary statistic of platelet count is calculated at each observation point. Moreover, the same analysis is performed about the variation | change_quantity from the platelet count before an administration start.
• Calculate summary statistics for each subject's maximum platelet count and maximum increase.
(2) Proportion of responder A patient whose platelet count has increased by 20,000 / μL or more from the start of administration and has reached 50,000 / μL or more is defined as a responder, and the following analysis is performed. If this standard is satisfied only after the initial combination of platelet preparations, it shall be a non-responder.
• Find the number and proportion of patients who met the responder criteria at least once during the study period.
・ Calculate the number of responder cases and their ratio at each observation point.
(3) Maintenance period of increase in platelet count Summary statistics are calculated for the following three periods with different criteria for maintaining increase in platelet count.
-The number of days that the platelet count was maintained at 50,000 / μL or more.
-The number of days that the platelet count was maintained at 70,000 / μL or more.
-The number of days when the platelet count increased by 20,000 / μL or more from the start of administration and maintained a value of 50,000 / μL or more.
(4) Evaluation In addition to the transition data of the number of platelets of Child-Pugh class C patients obtained in the above test and the clinical trials of M0623, M0625, M0626, and M0631 of Example 1, separately conducted clinical trials M0633 and To compare the transition data of platelet counts in patients with Child-Pugh category A and category B with M0634 added, and investigate similarities. Perform by Post-hoc analysis.

(Test Example 2) Evaluation of pharmacokinetics
Blood samples were collected at regular intervals after the administration of ruthrombopag to Child-Pugh class C patients, and the plasma concentration of ruthrombopag was measured. The results are shown in FIG. Number of examples, arithmetic mean (Mean), standard deviation (SD), and coefficient of variation (calculated as CV% = SD / Mean × 100), geometric mean and coefficient of variation (Geometric CV% = (exp (sd ² -1) Calculate by ^1/2 x 100. sd is the standard deviation of the value converted to the natural logarithm), median, minimum and maximum. The terminal phase elimination rate constant (λ _z ) and terminal phase elimination half-life (t _{1/2, z} ) are calculated from the measured plasma concentrations after the end of administration or after discontinuation.
C _max (ng / mL): Maximum plasma drug concentration
T _max (hr): Maximum plasma drug concentration time
AUC _0-τ (ng · hr / mL): Area under the plasma drug concentration-time curve from the time of administration by the trapezoidal method to the time of administration interval (24 hours) (using the Linear Up / Log Down method)
λ _z (hr ^-1 ): Terminal phase elimination rate constant
t _{1/2, z} (hr): terminal elimination half-life. Calculated as t _{1/2, z} = (ln2) / λ _z
CL / F (L / hr): Apparent whole body clearance. Calculated as CL / F = Dose / AUC _0-τ

In order to compare the pharmacokinetics of Rustrombopag between Child-Pugh classifications, the pharmacokinetic parameters (C _max , AUC _0-τ , λ _z , t _{1/2, z} and CL / F logarithmic transformations in the trial patients were compared. Value), and in a separate clinical study (M0633), Rustrombo for patients who have never been treated with Rustrombopag in an open-label study in patients with thrombocytopenia due to chronic liver disease of Child-Pugh classification A or B The analysis is performed by integrating the pharmacokinetic parameters when 3 mg of pug was administered once a day for 7 days. Analysis of variance is performed with the Child-Pugh classification as a fixed effect, and the ratio of the geometric mean of the parameters between the Child-Pugh classification and its 90% confidence interval are estimated.
Child-Pugh classification obtained by adding data of Child-Pugh classification C patients obtained in the above study and clinical trials of Example 1 to M0623, M0625, M0626, and M0631, plus clinical trials of M0633 and M0634 Compare data from A and Category B patients and examine similarities. Perform by Post-hoc analysis.

(Test Example 3) Safety evaluation
The following test items were performed before and after the administration of rusthrombopag to Child-Pugh Class C patients, and it was confirmed that there was no safety problem even if Rusthrombopag was administered to Child-Pugh Class C patients. .
1) Portal vein thrombus
Perform diagnostic imaging using CT or MRI to determine the presence or absence of portal vein thrombus.
2) Portal vein blood flow direction Measure portal vein blood flow direction (far hepatic, hepatophilic, stasis) by ultrasonic Doppler.
3) Blood pressure and pulse rate The blood pressure at rest (systolic blood pressure, diastolic blood pressure) and pulse are measured, and the presence or absence of abnormality from the start of administration is determined.
4) ECG examination
Check the presence or absence of ECG by 12-lead ECG.
5) Clinical examination Conduct clinical examination of the following items, and if it is within the range of the test standard value, it will be normal, and if it is outside the range, it will be abnormal.
5-1) Hematological examination (red blood cell count, hemoglobin, hematocrit, red blood cell count)
5-2) Blood biochemistry (AST, ALT, LDH, γ-GTP, ALP, total bilirubin, direct bilirubin, indirect bilirubin, soy protein, albumin, BUN, serum creatinine, Na, K, Cl, Ca)
5-3) Blood coagulation / fibrinolytic system test (PT-INR, activated partial thromboplastin time, antithrombin III activity, fibrinogen, fibrin degradation product, D-dimer)

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet Rustrombopag 15mg
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

Formulation Example 2 Capsules Rustrombopag 10mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.

Formulation Example 3 Granules Lustrombopag 30g
Lactose 265g
Magnesium stearate 5g
Are mixed well, compression molded, pulverized, sized, and sieved to obtain granules of appropriate size.

  The preparation described in Japanese Patent No. 5557146 can also be used in the present invention. Also, commercially available “Mulpreta (registered trademark) 3 mg” can be used in the present invention.

  The platelet production promoter containing rusthrombopag or a pharmaceutically acceptable salt thereof according to the present invention has an effect of increasing platelets even in patients with severe liver dysfunction (Child-Pugh classification C). Therefore, it is considered useful.

Claims (5)

  An agent for promoting platelet production containing ruthrombopag or a pharmaceutically acceptable salt thereof, characterized by being administered to a patient with severe liver dysfunction.   An agent for promoting platelet production containing ruthrombopag or a pharmaceutically acceptable salt thereof, characterized by being administered to adults including patients with severe liver dysfunction.   The platelet production promoter according to claim 2, wherein the adult, including a patient with severe liver dysfunction, is a patient with chronic liver disease who is scheduled for a waiting-time open procedure.   The platelet production promoter according to claim 2, wherein the adults including patients with severe liver dysfunction are thrombocytopenic patients.   The platelet production promoter according to any one of claims 1 to 4, wherein the severe liver dysfunction is a liver dysfunction classified as Child-Pugh classification C.

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