Pharmaceutical composition for the treatment of pulmonary artery hypertension

Abstract

The present invention relates to high-dose macitentan, i.e., propylsulfamic acid [5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide, or a pharmaceutically acceptable salt, solvate, hydrate, or morphological form thereof, or aprocitentan, for use in the treatment and / or prevention of pulmonary arterial hypertension (PAH). Furthermore, the present invention relates to the use of high-dose macitentan or aprocitentan for the manufacture of a medicament for the treatment and / or prevention of PAH, and to methods for the treatment and / or prevention of PAH comprising high-dose macitentan or aprocitentan. Furthermore, the present invention relates to dosing regimens for the treatment and / or prevention of PAH, and to combinations of one or more phosphodiesterase type 5 (PDE5) inhibitors, prostacyclin analogs, prostacyclin receptor agonists, or soluble guanylate cyclase stimulators. Wherein, the PAH is preferably mild or moderate PAH.Furthermore, the present invention relates to a pharmaceutical composition for treating PAH, comprising a high dose of macitentan or aprocitentan.

Description

[Technical Field]

[0001] The present invention relates to high doses of macitentan (INN), namely propylsulfamic acid [5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidine-2-yloxy)-ethoxy]-pyrimidine-4-yl]amide or pharmaceutically acceptable salts, solvates, hydrates or morphological forms, for use in the treatment and / or prevention of pulmonary arterial hypertension (PAH). Furthermore, the present invention relates to the use of high doses of macitentan for the manufacture of agents for the treatment and / or prevention of PAH, and to methods for the treatment and / or prevention of PAH, comprising administering high doses of macitentan to a patient. Furthermore, the present invention relates to administration regimens for the treatment and / or prevention of PAH, and to combinations of macitentan with one or more phosphodiesterase type 5 (PDE5) inhibitors, prostacyclin analogs, prostacyclin receptor agonists or soluble guanylate cyclase stimulants, wherein the PAH is preferably mild or moderate. Furthermore, the present invention relates to a pharmaceutical composition for the treatment of PAH containing a high dose of macitentan. [Background technology]

[0002] Pulmonary hypertension (PH) was first reported in 1891 when an autopsy of a patient who died suddenly revealed right ventricular hypertrophy and pulmonary arteriosclerosis without any apparent cause. Pulmonary arterial hypertension (PAH) is a subgroup of PH, a progressive disease characterized by increased pulmonary vascular resistance (PVR) as the underlying cause of increased right ventricular afterload and hypertrophy, which ultimately progresses to right ventricular dilation and abnormality, leading to premature death. According to the World Health Organization (WHO) classification, pulmonary hypertension (PH) is clinically classified into five groups: pulmonary artery hypertension (PAH) (Group 1), PH associated with left heart disease (Group 2), PH due to lung disease and / or hypoxia (Group 3), chronic thromboembolic PH and other pulmonary artery occlusion (Group 4), and PH with unclear and / or multifactorial mechanisms (Group 5) (Roger Hullin, Cardiovascular Medicine (2018), 21(7~8): Nos. 195-199; Simonneau et al., Hemodynamic definition and latest clinical classification of pulmonary hypertension. EUR.Respir.J.(2018), Dec 13.pii:1801913.doi:10.1183 / 13993003.01913-2018. [Electronic publication prior to print]).

[0003] This invention focuses on PAH, which is hemodynamically characterized by mean pulmonary artery pressure (PAP) > 20 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and the presence of PVR > 3 Wood units or greater.

[0004] In particular, the present invention focuses on PAH, which is hemodynamically characterized by a mean pulmonary artery pressure (PAP) ≥ 25 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and the presence of a PVR of > 3 Wood units or > 2 Wood units or greater.

[0005] The pathophysiology of PAH is characterized by an imbalance between molecules that mediate vasoconstriction (e.g., endothelin or thromboxane) and / or molecules that mediate vasodilation (e.g., prostacyclin and nitric oxide). Furthermore, the pro-cell division effects of these molecules are involved in specific pathological morphological changes in the pulmonary circulation and contribute to disease progression.

[0006] The currently available compounds approved for the specific treatment of PAH belong to three distinct groups: a) endothelin receptor antagonists, b) phosphodiesterase type 5 inhibitors (PDE5is) and soluble guanylate cyclase stimulants, and c) molecules that interfere with the prostacyclin pathway. Treatment with these compounds in combination with general measures is based on the REVEAL registry (Benza et al., REVEAL registry for pulmonary arterial hypertension). As shown in the long-term survival assessment from diagnosis, the 3-year survival rate after the initial diagnosis of idiopathic PAH has increased from 48% in the 1980s to 74% in the last 20 years. (CHEST (2012), 142(2), 448-456; and CHEST (2012), 141(2):354-362). [Overview of the project] [Means for solving the problem]

[0007] An object of the present invention is to provide agents and / or treatment regimens for pulmonary arterial hypertension (PAH). In particular, an object of the present invention is to provide agents and / or treatment regimens for the treatment of mild or moderate PAH. A further object of the present invention is to provide combination agents and / or treatments for PAH. [Brief explanation of the drawing]

[0008] [Figure 1] This is a dose-response curve showing the change in hemoglobin (HGB) as a function of the dose of macitentan administered to humans. [Modes for carrying out the invention]

[0009] The inventors have recognized that it is possible, safe, and effective to treat PAH patients with high doses of macitentan, despite the risk of clinically relevant hemoglobin reduction and / or increased blood pressure and / or edema or fluid retention. In particular, it is possible to reduce disease progression or even improve the disease state.

[0010] In the present invention, macitentan is defined as propylsulfamic acid [5-(4-bromophenyl)-6-[2-(5-bromopyrimidine-2-yloxy)-ethoxy]pyrimidine-4-yl]amide, i.e., a compound of formula (I).

[0011] [ka] Alternatively, this may include pharmaceutically acceptable salts, solvates, hydrates, or morphological forms.

[0012] Macitentan is a drug for two endothelin (ET) receptor subtypes, ET A and ET B It is an endothelin receptor antagonist (ERA) that acts as an antagonist to macitentan (Kholdani et al., for the treatment of pulmonary arterial hypertension). Vasc. Health Risk Manag. (2014), 10, 665-673). In humans, the half-life is approximately 16 hours, and steady state is reached on the third day of administration (Bruderer et al., Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans). Xenobiotica (2012), 42(9), 901-910). It is slowly absorbed into the plasma (Sidharta et al., Macitentan: A human invasion study of a novel endothelin receptor antagonist. Eur. J. Clin. Pharmacol. (2011), 67, 977-984). The active metabolite ACT-132577, which reaches its peak plasma concentration approximately 30 hours after the first dose is administered, contains maciten. The sputum dealkylate is administered and has a half-life of approximately 48 hours. ACT-132577 has a lower affinity for the ET receptor than its parent compound (Iglarz et al., Pharmacology of macitentan, an orally active tissue-targeted biendothelin receptor antagonist. J. Pharmacol. Exp. Ther. (2008) 327(3), 736-745), and maintains higher plasma concentrations than macitentan. Both compounds can be excreted from the body through urine or feces.

[0013] The maximum or near-maximum efficacy of macitentan in rats has been reported to be 10 mg / kg (European Medicines Agency, European Public Assessment Report for Opsumit, Procedure No. EMEA / H / C / 002697 / 0000 (2013)). The maximum effective dose of macitentan in rats has also been reported to be 30 mg / kg (Id.; e.g., Iglarz et al., Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension. Life Sci. (2014), 118, 333-339). See also Kunita-Takanezawa et al., Novel dual endothelin receptor antagonist macitentan reverses severe pulmonary arterial hypertension in rats. J. Cardiovasc. Pharmacol. (2014), 64(5):473-480).

[0014] In multiple escalating dose trials evaluating 1 mg, 3 mg, 10 mg, and 30 mg doses of macitentan in healthy human subjects, steady-state plasma ET-1 concentrations showed a dose-dependent increase and did not increase further beyond the 10 mg oral dose, demonstrating blockade at this dose. (Id at 40). The evaluators concluded that the 10 mg dose appeared to be near the plateau of the pharmacological effect. (Id at 48). The European Medicines Agency and the US Food and Drug Administration have approved a 10 mg once-daily oral dose of macitentan for the treatment of pulmonary arterial hypertension patients. (EMA at 2, Summary of Product Characteristics for Opsumit (October 29, 2019); FDA at 1, Prescribing Information for Opsumit (April 2019)).

[0015] Some aspects of the present invention will be described below.

[0016] (a) One aspect of the present invention relates to macitentan for use in the treatment and / or prevention of pulmonary arterial hypertension (PAH) in humans, and the dose of macitentan is greater than 20 mg per day to 300 mg per day or less, for example, greater than 20 mg per day to less than 250 mg per day. Preferably, the dose is 25 mg to 200 mg.

[0017] According to a more preferred aspect, these doses are applied once a day.

[0018] In the present invention, PAH is defined as human pulmonary arterial hypertension.

[0019] The present invention focuses on PAH that is hemodynamically characterized by the presence of mean pulmonary artery pressure (PAP) > 20 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and 3 Wood units, or > 2 Wood units, all measured at rest. In addition to the above hemodynamic characterization, PAH is clinically characterized by the absence of excessive left heart disease, severe lung disease, or known chronic thromboembolic disease.

[0020] Specifically, the focus of the present invention is hemodynamically characterized by the following right heart catheterization method. ● Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg ● Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg ● 3 Wood units, or pulmonary vascular resistance greater than (>) 2 Wood units.

[0021] In addition to the above hemodynamic characterization, PAH is clinically characterized by the absence of excessive left heart disease, severe lung disease, or known chronic thromboembolic disease.

[0022] As described above, macitentan is currently administered as an oral dose of 10 mg once daily. However, in the present invention, it is suggested that administering a high dose of macitentan improves the disease state, prevents the occurrence of disease exacerbation, improves or stabilizes the WHO functional class, improves long-term survival, and / or reduces the hospitalization rate. Advantageously, for example, compared to bosentan, the side effects on liver function are fewer, and hepatotoxicity is not at all or not significant.

[0023] A further advantage is that there is no further clinically relevant decrease in hemoglobin, no further clinically relevant decrease in blood pressure, and / or no further clinically relevant increase in edema / fluid retention.

[0024] (b) Another aspect of the present invention relates to macitentan for use in the treatment and / or prevention of pulmonary arterial hypertension (PAH) according to aspect (a), wherein the PAH is mild or moderate PAH, preferably moderate PAH.

[0025] Surprisingly, it has been found that in mild and moderate PAH, the disease state can be improved or stabilized. Specifically, in mild and moderate patients, the WHO functional class can be improved. The functional capacity measured by the 6-minute walk test can also be improved.

[0026] The term "mild PAH" is approximately equivalent to WHO functional classes I and II.

[0027] The term "moderate PAH" is roughly equivalent to WHO functional class III.

[0028] In contrast, WHO functional class IV is equivalent to severe PAH.

[0029] The WHO Functional Class (WHOFC) is generally known and is defined as follows: WHOFC I: No symptoms of pulmonary hypertension during exercise or at rest. It is rare for patients to remain in Class I. Patients screened for high risk factors for developing PAH, such as scleroderma or a family history of PAH, may rarely be diagnosed as Class I. More often, this classification is used to describe patients who were previously in Class II or III but showed a substantial response to treatment and improved to Class I.

[0030] WHOFC II: No symptoms at rest, but discomfort, fatigue, or shortness of breath during normal activities such as climbing stairs, grocery shopping, or making the bed.

[0031] WHOFC III: Patients may be asymptomatic at rest, but their normal activities are significantly limited by shortness of breath, fatigue, or near-fainting. Patients in this class have difficulty performing normal household chores at times and require breaks during daily living activities.

[0032] WHOFC IV: Severe symptoms at rest or associated with any activity. Patients in this class may faint in response to activity or while hunched over. Many patients in this class are also excessively overloaded with edema of the feet and ankles due to right heart failure.

[0033] A more detailed assessment of mild PAH is determined as follows: (d. Mild): Meets at least three of the following criteria: -WHOFC I or II, -6-minute walking distance (6MWD) > 440m, - B-type natriuretic peptide (BNP) < 50 ng / L or N-terminal pro-B-type natriuretic peptide (NT-proBNP) < 300 ng / L; or RAP < 8 mg HG, -CI≧2.5L / min / m 2 Or SvO2 > 65%; -(d) Does not meet any of the criteria for severe condition.

[0034] A more detailed assessment of severe PAH is determined as follows: (d) Severe: Meets at least two of the following characteristics, including CI or SvO2. -WHOFC IV, -6MWD<165 meters, -BNP > 300 ng / L or NT-proBNP > 1400 ng / L; or RAP > 14 mg HG -CI < 2.0 L / min / m 2 Alternatively, SvO2 < 60%.

[0035] A more detailed assessment of moderate PAH is determined as follows: The aforementioned assessments of the (d) moderate, (d) mild, and (d) severe criteria do not allow for classifying a patient's PAH as either mild or severe PAH.

[0036] Preferably, the concentration of NT-proBNP rather than the concentration of BNP is determined and used to determine whether the patient has mild, moderate, or severe PAH according to the more detailed evaluation definitions described above.

[0037] BNP is measured as follows: Plasma samples are collected, frozen in plastic EDTA tubes (below -20°C), and analyzed by immunochemical assay (ICMA). The principle of this ICMA assay is as follows: ● Use a commercially available kit (Triage® BNP test) with the following three working solutions / suspensions. ○S1a: Paramagnetic particles coated with mouse whole-clonal anti-human BNP antibody suspended in Tris-buffered saline solution (150 mM NaCl, 50 mM Tris-HCl, pH 7.6 aq. solution), containing bovine serum albumin (BSA), 0.1% ProClin™ 300 (0.60-1.00% 2-methyl-4-isothiazolin-3-1 and 2.10-2.80% 5-chloro-2-methyl-4-isothiazolin-3-1 aq. solution) and <0.1% sodium azide; ○S1b: Contains purified mouse and goat IgG, bovine serum albumin (BSA), 0.1% ProClin™ 300 (0.60-1.00% 2-methyl-4-isothiazolin-3-1 and 2.10-2.80% 5-chloro-2-methyl-4-isothiazolin-3-1 aq. solution) and <0.1% sodium azide in Tris-buffered saline solution (150 mM NaCl, 50 mM Tris-HCl, pH 7.6 aq. solution), and <0.1% sodium azide. ○S1c: Contains mouse monoclonal anti-human BNP antibody-alkaline phosphatase conjugate (pH 7.4; 137 mmol / L NaCl, 2.7 mmol / L KCl, 10 mmol / L Na2HPO4 and 1.8 mmol / L KH2PO4) in PBS-buffered physiological saline solution, bovine serum albumin (BSA), 0.1% ProClin™ 300 (0.60-1.00% 2-methyl-4-isothiazolin-3-1 and 2.10-2.80% 5-chloro-2-methyl-4-isothiazolin-3-1 solution) and <0.1% sodium azide. ●A blood sample (500 μL) was collected from the patient and placed in a plastic blood draw tube containing K2EDTA as an anticoagulant. The blood sample was then gently inverted several times. It should be mixed by doing so. ●Place suspension S1a and solution S1c in a reaction vessel, and add 55 μL of blood sample to it. ●After incubation in the reaction vessel, a magnetic field is used to retain the material bonded to the solid phase, and the unbonded material is washed away using solution S1b. Next, the chemiluminescent substrate, Lumi-Phos(registered trademark) 530 (Chemical The substance (Abstracts Substance No. 146239-76-1) is added to the reaction vessel, and the light generated by the reaction is measured with an illuminometer. Since the obtained light is proportional to the BNP concentration, the BNP concentration in the sample can be determined. ● To ensure the accuracy of ICMA assay results, illuminometers should be regularly calibrated with commercially available reference solutions.

[0038] NT-proBNP is measured as follows: Serum or plasma samples are collected, and if collected within 3 days, transported at ambient temperature or centrifuged and frozen in a red top tube, and analyzed by electrochemiluminescence immunoassay (ECLIA). The principle of this ECLIA assay is as follows: ●Use a commercially available kit containing the following three active solutions / suspensions. ○S1: A suspension (6.5 mL) of streptavidin-coated fine particles (0.72 mg / mL) containing a preservative; ○S2: A solution of anti-NT-proBNP-Ab-biotin (9 mL) containing biotinylated monoclonal anti-NT-proBNP antibody (mouse) (1.1 μg / mL), phosphate buffer 40 mmol / L, pH 5.8, and a preservative, and ○S3: A solution (9 mL) of anti-NT-proBNNP Ab-Ru(bpy) containing tris(2,2'-bipyridyl)ruthenium(II) complex (Ru(bpy)) (1.1 μg / mL), phosphate buffer 40 mmol / L, pH 5.8, and a monoclonal NT-proBNP-specific antibody labeled with a preservative. ● First, incubate the sample (15 μL) with solutions S2 and S3. The biotinylated monoclonal NT-proBNP-specific antibody and the monoclonal NT-proBNP-specific antibody labeled with a ruthenium complex will form a sandwich complex. Next, a second incubation is performed, during which, after the addition of suspension S1, the complex binds to the solid phase via the interaction between biotin and streptavidin. ● The reaction mixture is attracted to a measuring cell in which fine particles are magnetically trapped on the surface of the electrodes. Unbound material is then removed. The application of voltage to the electrodes then induces chemiluminescent emission, which is measured by a photomultiplier. ●The results are determined based on a calibration curve using a commercially available reference solution.

[0039] CI is measured as follows: CI reflects the blood flow through the heart (liters / minute), is called cardiac output (CO), and is standardized to the patient's body surface area (BSA). Therefore, CI is liters / minute / meter 2 It is expressed as follows. Right cardiac catheterization (RHC) is a standard procedure used to diagnose PAH. It is an invasive procedure in which a catheter is inserted through the superior vena cava, then advanced to the right side of the heart, and then advanced into the pulmonary artery. There are different methods for measuring CI, but the most common methods are the Fick cardiac index method or the thermodilution cardiac index method. These are standardized and well-established methods. The most common method is the thermodilution method. According to this invention, the thermodilution (TD) method is a specific method used to measure CI. TD determines CO based on how quickly a set volume of fluid (typically room temperature, i.e., 25°C) moves from the right atrium [injected into the proximal port of the pulmonary artery (PA) catheter] to the PA (detected by a thermal sensor close to the distal tip of the PA catheter). The area under the curve (AUC) of the temperature change is generated. This can be repeated at least three times, and then the average value is calculated, but the values ​​should be within (+ / -) 10-15% of each other to make these measurements valid. It should be. The curve should also be evaluated to ensure that the flow is smooth without abrupt changes in the curve that could suggest erroneous injection or measurement. Based on the obtained mean AUC and patient BSA, it is defined as follows: BSA = √[(height in cm × weight in kg) / 3600] Calculate CI.

[0040] RAP is measured as follows: RAP (sometimes called mRAP, i.e., mean RAP) is also measured during the RHC procedure as outlined above to measure CI. At the tip of the catheter is a pressure sensor that is inserted into a vein that forms its way on the right side of the heart. The sensor measures the pressure when the catheter tip is in the right atrium, and the measured pressure is the RAP. This is a single measurement.

[0041] SvO2 is measured as follows: SvO2 is also measured during the RHC procedure as outlined above to measure CI. When the catheter tip is in the central vein or right atrium, blood is drawn and the "concentration" / "content" of oxygen in that blood sample (partial pressure of oxygen in the blood) is analyzed using a standard blood gas analyzer / sensor, and the percentage of oxygenation in the blood sample is SvO2. It is also a single measurement.

[0042] For a more detailed assessment, mild and moderate PAH can be defined according to an algorithm based on a registry (REVEAL registry) for evaluating early and long-term PAH disease management. The algorithm can be described as including the following steps: (i) Determination and assignment of patients to WHO Group I subgroup +APAH-CTD (PAH associated with connective tissue disease) score of +1, APAH-PoPH score of +2 (PAH is associated with portal pulmonary hypertension), A +2 score for FPAH (now called familial PAH, or hereditary PAH); A score of 0 for any other subgroup of PAH; (ii) Demographics and determination and allocation of coexistence A +1 score for kidney failure, >A male age of 60 with a +2 score, A score of 0 compared to other patients; (iii) Determination and assignment of WHO functional classes -2 score for WHOFC I 0 score for WHOFC II +1 score for WHOFG III +2 score for WHOFG IV (iv) Determination and assignment of important indicators A score of +1 for SBP (systolic blood pressure) < 110 mmHg. +1 score for HR (heart rate) > 92 BPM (beats per minute). A score of 0 for any other case; (v) Determination and allocation of 6-minute walking distance -1 score for ≥440 meters, <165 meters +1 score, A score of 0 for any other case; (vi) Determination and allocation of BNP (brain natriuretic peptide) BNP < 50 pg / mL, -2 score. BNP > 180 pg / mL = +1 score. BNP levels of 50 pg / mL to 180 pg / mL with a score of 0; (vii) Determination and assignment of echocardiograms A +1 score for pericardial effusion, A score of 0 for any other case; (viii) Pulmonary function tests and assignments A score of -1 for predicted DLCO ≥ 80% (the pulmonary diffusion capacity of carbon monoxide), A score of +1 for a predicted DLCO of ≤32%. A score of 0 for predicted DLCO% between 32% and 80%; (ix) Heating and allocation of the right side of the heart RAP (Mean Right Arterial Pressure) > 20 mmHg, +1 score within the last year. PVR (Pulmonary Vascular Resistance) > 32: +2 score in Wood units. A score of 0 for any other case; (x) Summarize the scores obtained in steps (i) to (ix) and add the number 6; (xi) Mild PAH is assigned a score from 1 to 7. Moderate PAH is assigned a score of 8 or 9.

[0043] In the algorithm above, "+" means addition and "-" means subtraction.

[0044] Wood units are a simplified system of measures for measuring pulmonary vascular resistance (PVR) using pressure increments. PVR is measured by subtracting the pulmonary artery wedge pressure from the mean pulmonary artery pressure and dividing by cardiac output in liters / min.

[0045] Therefore, mild PAH is associated with scores of 1-7, and moderate PAH is associated with scores of 8 or 9.

[0046] Further definitions are explicitly stated in the ESC / ERS Guidelines, European Heart Journal (2016), 37, 67-119.

[0047] Genetic inheritance of PAH has been reported in approximately 6%–10% of PAH patients, and mutations in BMPR2 (bone morphogenesis protein receptor type-2) have been identified in 50%–90% of these individuals. Mutations in BMPR2 in familial pulmonary hypertension (FPAH) are characterized by genetic prediction and incomplete penetrance. FPAH is also called HPAH (hereditary PAH). The phenotype is not expressed in all generations, but when expressed, it occurs at an early age and is associated with a more severe and rapidly progressive disease. Many other gene mutations have been identified as being associated with familial (hereditary) PAH, but these are far less common than BMPR2 mutations. (Morrell et al., Eur.Respir.J.(2018), Dec 13.pii:1801899.doi:10.1183 / 13993003.01899-2018.[Electronic publication prior to print]).

[0048] In this invention, APAH-CTD (PAH associated with connective tissue disease) is characterized by PAH in individuals with autoimmune diseases also known as connective tissue diseases. The most common connective tissue diseases associated with PAH are scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus / SLE), mixed connective tissue disease, and Sjögren's disease.

[0049] In this invention, APAH-PoPH (PAH associated with portal pulmonary hypertension) is characterized by PAH associated with portal venous hypertension. Portal venous hypertension is defined as an increase in pressure within the portal vein, as evidenced by an increase in the pressure gradient between the portal vein and the hepatic vein greater than 5 mmHg (clinically significant when the pressure gradient is ≥10 mmHg). The portal vein carries blood from the gastrointestinal system to the liver. This more often occurs in the presence of progressive liver disease that causes portal venous hypertension, whereas portal venous pulmonary hypertension can occur in the absence of liver disease, as long as portal hypertension is present.

[0050] PAH associated with portal vein hypertension is commonly referred to as PoPH. This entity, characterized by abnormal pulmonary vasodilation and hypoxemia, should not be confused with hepatopulmonary syndrome. However, overlap between the two conditions can occur. As the term suggests, PoPH is associated with the presence of portal vein hypertension as defined above, without necessarily the presence of liver disease. However, since cirrhotic liver disease is the cause of most portal vein hypertension, PoPH is most frequently encountered in patients with cirrhosis.

[0051] A complete diagnostic workup, including right cardiac catheterization (RHC), is required to assess the severity of the disease, hemodynamic aspects, and other potential causes of PH, including lung disease, LHD, or chronic thromboembolic disease (ESC / ERS Guidelines, European). Heart Journal (2016), 37,67~119).

[0052] In this invention, renal failure is defined as 90 mL / min / 1.73 m². 2Characterized by a glomerular filtration rate (GFR) below. GFR is obtained by obtaining the standardized serum creatinine concentration (SCr) from the patient and using the following MDRD equation. GFR = 175 × SCr− 1.154 × age -0.203 × (0.742 if female) × (1.21 if black)

[0053] The GFR obtained according to the above equation is expressed in mL / min per 1.73 m 2 of body surface area. If the patient's body surface area is different from 1.73 m 2 the value obtained for GFR via the above MDRD equation should be converted accordingly.

[0054] Pericardial effusion is the collection of fluid around the heart. Normally, it should be very thin and typically invisible to the normal eye, and there should be a layer of fluid (a fibrous layer that surrounds and protects the heart) that acts as a lubricant to prevent friction between the heart and the pericardium. In the setting of advanced PH (as well as many other diseases), the fluid accumulates and forms a collection around the heart defined as pericardial effusion. The presence of such effusion means advanced PH and right heart dysfunction / failure, so the prognosis tends to be poor.

[0055] DLCO is measured by pulmonary function tests. These tests are performed as described in Graham et al., 2017 ERS / ATS Standards for Single Breath Carbon Monoxide Uptake in the Lung. Eur. Respir. J. (2017), 49, 1600016.

[0056] RHC is invasive and typically an outpatient procedure involving inserting a catheter through a central vein and then passing through the right heart chambers to reach the pulmonary artery. During this procedure, different measurements are taken, including pressure and blood flow called cardiac output.

[0057] (c) Another aspect of the present invention relates to macitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the dose of macitentan is 60 to 90 mg per day. Preferably, the dose is 65 to 85 mg per day, more preferably 70 to 80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60 to 85 mg, 60 to 80 mg, or 60 to 75 mg per day. Doses of 65 to 90 mg or 65 to 75 mg per day are also disclosed. A more preferred range is 72 to 78 mg per day. According to the more preferred aspect, these doses are applied once daily.

[0058] In a preferred embodiment, these doses are for mild or moderate PAH, preferably moderate PA Related to macitentan for use in the treatment and / or prevention of H.

[0059] (d) Further embodiments of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to embodiment (a) or (b), wherein the dose of macitentan is 25 to 50 mg per day. Preferably, the dose is 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 25 to 45 mg per day or 25 to 40 mg per day. Doses of 30 to 50 mg per day or 30 to 40 mg per day are also disclosed. A more preferred range is 36 to 39 mg per day. According to the more preferred embodiment, these doses are applied once daily.

[0060] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0061] (e) Further embodiments of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to embodiment (a) or (b), wherein the dose of macitentan is 110 to 200 mg per day. Preferably, the dose is 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 110 to 175 mg per day, 110 to 160 mg per day, or 110 to 150 mg per day. Doses of 125 to 160 mg or 140 to 175 mg per day are also disclosed. A more preferred range is 145 to 155 mg per day. According to the more preferred embodiment, these doses are applied once daily.

[0062] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0063] (f) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the dose of macitentan is 60 to 90 mg twice daily. Preferably, the dose is 65 to 85 mg twice daily, more preferably 70 to 80 mg twice daily, and most preferably 75 mg twice daily. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60 to 85 mg twice daily, 60 to 80 mg twice daily, or 60 to 75 mg twice daily. Doses of 65 to 90 mg twice daily, or 65 to 75 mg twice daily are also disclosed. A more preferred range is 72 to 78 mg twice daily.

[0064] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0065] (g) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the dose of macitentan is 25 to 50 mg twice daily, preferably 30 to 45 mg twice daily, more preferably 35 to 40 mg twice daily, and most preferably 37.5 mg twice daily. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 25 to 45 mg twice daily, or 25 to 40 mg twice daily. Doses of 30 to 50 mg twice daily, or 30 to 40 mg twice daily are also disclosed. A more preferred range is 36 to 39 mg twice daily. ru.

[0066] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0067] (h) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), where the dose of macitentan is gradually increased from 10 mg per day, followed by 25 to 50 mg per day, preferably 37.5 mg per day, and optionally followed by 60 to 90 mg per day, preferably 75 mg per day. Therein, “followed by 25 to 50 mg per day” means preferably that the dose is 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e., the dose may also be 25 to 45 mg per day or 25 to 40 mg per day. Doses of 30 to 50 mg per day or 30 to 40 mg per day are also disclosed. A more preferred range is 36 to 39 mg per day. Please understand that any dose escalation to a higher dose can be reversed to a lower dose if the higher dose is not tolerated.

[0068] Furthermore, the phrase "optionally followed by 60-90 mg per day" means that preferably the dose is 65-85 mg per day, more preferably 70-80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Doses of 65-90 mg or 65-75 mg per day are also disclosed. A more preferred range is 72-78 mg per day. It should be understood that any increase up to a higher dose can be reversed to a lower dose if the higher dose is not tolerated.

[0069] In a more preferred embodiment, these doses are administered once daily.

[0070] If present, the dose of macitentan for the treatment of PAH is 10 mg per day. Patients receiving this dose may receive immediate dose escalations up to 37.5 mg per day, optionally followed by 75 mg per day.

[0071] A further aspect of the present invention relates to macitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the dose of macitentan is gradually increased from 10 mg per day, followed by 25 to 50 mg per day, preferably 37.5 mg per day, optionally followed by 60 to 90 mg per day, preferably 75 mg per day, optionally followed by 110 to 200 mg per day, preferably 150 mg per day.

[0072] The phrase "optionally followed by 110-200 mg per day" means that preferably the dose is 125-175 mg per day, more preferably 140-160 mg per day, and most preferably 150 mg per day. Each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 110-175 mg per day, 110-160 mg per day, or 110-150 mg per day. Doses of 125-160 mg or 140-175 mg per day are also disclosed. A more preferred range is 145-155 mg per day. According to a more preferred embodiment, these doses are applied once daily.

[0073] In a preferred embodiment, these doses are for mild or moderate PAH, preferably moderate PA Related to macitentan for use in the treatment and / or prevention of H.

[0074] (i) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the dose of macitentan is gradually increased from 10 mg per day, followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily.

[0075] The phrase "optionally followed by 60-90 mg per day" means that preferably the dose is 65-85 mg per day, more preferably 70-80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Doses of 65-90 mg or 65-75 mg per day are also disclosed. A more preferred range is 72-78 mg per day. It should be understood that any increase up to a higher dose can be reversed to a lower dose if the higher dose is not tolerated.

[0076] In a more preferred embodiment, these doses are administered once daily.

[0077] Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the dose of macitentan is gradually increased from 10 mg per day, followed by 60-90 mg per day, preferably 75 mg per day, or 37.5 mg twice per day, optionally followed by 110-200 mg per day, preferably 150 mg per day.

[0078] The phrase "optionally followed by 110-200 mg per day" means that preferably the dose is 125-175 mg per day, more preferably 140-160 mg per day, and most preferably 150 mg per day. Each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 110-175 mg per day, 110-160 mg per day, or 110-150 mg per day. Doses of 125-160 mg or 140-175 mg per day are also disclosed. A more preferred range is 145-155 mg per day. According to a more preferred embodiment, these doses are applied once daily.

[0079] If present, the dose of macitentan for the treatment of PAH is 10 mg per day. Patients receiving this dose may receive immediate dose escalations up to 75 mg per day or 150 mg per day.

[0080] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0081] (j) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (h), wherein the dose of macitentan is escalated from 10 mg once daily, preferably for 15 to 45 days, followed by 25 to 50 mg once daily, preferably 37.5 mg once daily, preferably for 15 to 45 days, and optionally followed by 60 to 90 mg once daily, preferably 75 mg once daily, or 37.5 mg twice daily. It should be understood that any escalation to a higher dose may be reversed to a lower dose if the higher dose is not tolerated.

[0082] In this context, the term "15-45 days" preferably means 20-40 days, more preferably 21-3 days. This means 5 days, most preferably 28-30 days, or about one month.

[0083] Furthermore, the phrase "nextly, 25-50 mg per day" means that preferably the dose is 30-45 mg per day, more preferably 35-40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e., the dose may also be 25-45 mg per day or 25-40 mg per day. Doses of 30-50 mg per day or 30-40 mg per day are also disclosed. A more preferred range is 36-39 mg per day.

[0084] Furthermore, the phrase "nextly, 60-90 mg per day" means that preferably it is 65-85 mg per day, more preferably 70-80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Doses of 65-90 mg or 65-75 mg per day are also disclosed. A more preferred range is 72-78 mg per day, or 36-39 mg twice a day.

[0085] In a more preferred embodiment, these doses are administered once daily.

[0086] A further aspect of the present invention relates to macitentan for use in the treatment and / or prevention of PAH according to aspect (h), wherein the dose of macitentan is escalated from 10 mg once daily, preferably for 15 to 45 days, followed optionally by 25 to 50 mg once daily, preferably 37.5 mg once daily, preferably for 15 to 45 days, followed optionally by 60 to 90 mg once daily, preferably 75 mg once daily, or 37.5 mg twice daily, preferably for 15 to 45 days, followed optionally by 110 to 200 mg once daily, preferably 150 mg per day.

[0087] The phrase "optionally followed by 110-200 mg per day" means that preferably the dose is 125-175 mg per day, more preferably 140-160 mg per day, and most preferably 150 mg per day. Each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 110-175 mg per day, 110-160 mg per day, or 110-150 mg per day. Doses of 125-160 mg or 140-175 mg per day are also disclosed. A more preferred range is 145-155 mg per day. According to a more preferred embodiment, these doses are applied once daily.

[0088] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0089] (k) A further aspect of the present invention is macitentan for use in the treatment and / or prevention of PAH according to aspect (i), wherein the dose of macitentan is 10 mg once daily, preferably increased gradually for 15 to 45 days, followed by 60 to 90 mg per day, preferably 75 mg once daily, or 37.5 mg twice daily.

[0090] In this context, the term "15-45 days" preferably means 20-40 days, more preferably 21-35 days, and most preferably 28-30 days, i.e., about one month.

[0091] The phrase "Next, 60-90 mg per day" means that the dose is preferably 65-85 mg per day, more preferably 70-80 mg per day, and most Preferably, the dose is 75 mg per day. Each of the lower limits disclosed above may be combined with each of the upper limits, so that the dose may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Doses of 65-90 mg or 65-75 mg per day are also disclosed. A more preferred range is 72-78 mg per day, or 36-39 mg twice a day.

[0092] Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to (i), wherein the dose of macitentan is escalated from 10 mg once daily, preferably for 15 to 45 days, followed optionally by 60 to 90 mg once daily, preferably 75 mg once daily, or 37.5 mg twice daily, preferably for 15 to 45 days, followed optionally by 110 to 200 mg per day, preferably 150 mg per day. The phrase "optionally followed optionally by 110 to 200 mg per day" means preferably that the dose is 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. Each of the lower limits disclosed above may be combined with each of the upper limits, meaning that the dose may also be 110–175 mg per day, 110–160 mg per day, or 110–150 mg per day. Doses of 125–160 mg or 140–175 mg per day are also disclosed. A more preferred range is 145–155 mg per day.

[0093] In a more preferred embodiment, these doses are administered once daily.

[0094] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0095] (l) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH as described in any one of aspects (a) to (d), wherein the dose of macitentan is escalated to 25 to 50 mg per day, preferably 37.5 mg per day, preferably for 15 to 45 days, optionally followed by 60 to 90 mg per day, preferably 75 mg per day, provided that the patient is already being treated with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that any escalation to a higher dose may be reversed to a lower dose if the higher dose is not tolerated.

[0096] In this context, the term "15-45 days" preferably means 20-40 days, more preferably 21-35 days, and most preferably 28-30 days, i.e., about one month.

[0097] Furthermore, the phrase "nextly, 25-50 mg per day" means that preferably the dose is 30-45 mg per day, more preferably 35-40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e., the dose may also be 25-45 mg per day or 25-40 mg per day. Doses of 30-50 mg per day or 30-40 mg per day are also disclosed. A more preferred range is 36-39 mg per day.

[0098] Furthermore, the phrase "nextly, 60-90 mg per day" means preferably 65-85 mg per day, more preferably 70-80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Doses of 65-90 mg or 65-75 mg per day are also disclosed. A more preferred range is 72-78 mg per day, or 36-39 mg twice a day.

[0099] It should be understood that the dose of macitentan can be optionally increased further by 110-200 mg per day. The dose is then gradually increased as in (i), (j), or (k).

[0100] In a more preferred embodiment, these doses are administered once daily.

[0101] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0102] (m) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH as described in any one of aspects (a) to (c), wherein the dose of macitentan is 60 to 90 mg per day, preferably 75 mg per day, and the patient is already being treated with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan.

[0103] The phrase "60-90 mg per day" preferably means that the dose is 65-85 mg per day, more preferably 70-80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Doses of 65-90 mg or 65-75 mg per day are also disclosed. A more preferred range is 72-78 mg per day, or 36-39 mg twice a day.

[0104] It should be understood that the dose of macitentan can be optionally increased further by 110-200 mg per day. The dose is then gradually increased as in (i), (j), or (k).

[0105] In a more preferred embodiment, these doses are administered once daily.

[0106] In a preferred embodiment, these doses relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0107] (n) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH as described in any one of aspects (a) to (m), wherein macitentan is combined with a PDE5 inhibitor and / or a prostacyclin analog and / or a prostacyclin receptor agonist and / or a soluble guanylate cyclase stimulant.

[0108] Inhibition of phosphodiesterase type 5, a cyclic guanosine monophosphate (cGMP) degrading enzyme, leads to vasodilation via the NO / cGMP pathway at sites expressing this enzyme. Since the pulmonary vascular system contains a significant amount of phosphodiesterase type 5, the potential clinical effects of phosphodiesterase type 5 inhibitors (PDE5is) are being investigated in PAH. In addition, PDE5is exhibit antiproliferative effects (ESC / ERS guidelines; European Heart Journal (2016), 37, 67-119).

[0109] Prostacyclins are primarily produced by endothelial cells and induce potent vasodilation of all vascular beds. This compound is the most potent endogenous inhibitor of platelet aggregation and appears to possess both cytoprotective and antiproliferative activity. The prostacyclin metabolic pathway is dysregulated. The full picture shows that prostacyclin is used in patients with PAH, as assessed by the expression of pulmonary artery prostacyclin synthase and the reduction of prostacyclinuria metabolites. The clinical use of prostacyclin in PAH patients has been expanded by the synthesis of stable analogs that have different pharmacokinetic properties but share qualitatively similar pharmacokinetic effects (ESC / ERS Guidelines; European Heart Journal (2016), 37, 67-119).

[0110] No drug-drug interactions have been observed with macitentan or its active metabolite, ACT-132577, to date.

[0111] For example, 10 mg of macitentan per day showed no effect on the pharmacokinetics of 1 mg of rosuvastatin, suggesting that the BCRP transporter was not inhibited. BCRP is an efflux pump located in the intestine, liver tumor membrane, and kidney, and is exposed to intracellular drug concentrations in the liver and kidney.

[0112] Masitentane and ACT-132577 have EC values ​​of 1.1-1.2 μM and 7.2-8.7 μM, respectively. 50Human PXR cells with specific values ​​were activated. In human hepatocytes, both compounds induced a concentration-dependent increase in CYP3A4 mRNA and enzyme activity.

[0113] Based on PK subtests, the predicted peak plasma concentrations of macitentan and ACT-132577 in PAH patients receiving 75 mg per day are expected to be approximately 5 μM and 14 μM, respectively, assuming dose linearity. Considering high protein binding, free plasma concentrations are expected to range from 0.02 μM to 0.07 μM for macitentan and ACT-132577, respectively. These unbound concentrations of macitentan and ACT-132577 are unlikely to result in any inhibition of BCRP in the liver or kidneys, or induction of CYP3A4 enzyme in the liver.

[0114] Therefore, the dose of macitentan may be 60 to 90 mg per day in embodiment (n). Preferably, the dose is 65 to 85 mg per day, more preferably 70 to 80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60 to 85 mg, 60 to 80 mg, or 60 to 75 mg per day. Doses of 65 to 90 mg or 65 to 75 mg per day are also disclosed. A further preferred dose range is 72 to 78 mg per day.

[0115] Furthermore, the dose of macitentan may be gradually increased from 10 mg per day, followed by 25-50 mg per day, preferably 37.5 mg per day, followed by 60-90 mg per day, preferably 75 mg per day, and optionally followed by 100-200 mg per day, preferably 150 mg per day.

[0116] In a preferred embodiment, these combinations relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0117] (o) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (n), wherein the PDE5 inhibitor is selected from sildenaphysil, tadalafil, vardenafil, and udenafil; the prostacyclin analog is selected from epoprostinol, treprostinil, iloprost, and beraprost; the prostacyclin receptor agonist is selected from selexipag and larinupag; and the soluble guanylate cyclase stimulant is selected from riociguat and biriciguat.

[0118] Here, macitentan has an administration or administration regimen as described in any one of embodiments (a) to (l) and (n). In preferred embodiments, these doses relate to macitentan for use in the treatment and / or prophylaxis of mild or moderate PAH.

[0119] In a preferred embodiment, these combinations relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0120] (p) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (n) or (o), wherein macitentan is combined with tadalafil and / or selexipag or larinupag. Preferably, macitentan is combined with tadalafil and / or selexipag.

[0121] Here, macitentan has an administration or administration regimen as described in any one of embodiments (a) to (k) and (n). In preferred embodiments, these doses relate to macitentan for use in the treatment and / or prophylaxis of mild or moderate PAH.

[0122] In a preferred embodiment, these combinations relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0123] (q) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH according to aspect (p), wherein tadalafil is used in a dose of 20 to 40 mg per day, preferably 40 mg per day, where applicable; selexipag is used in a dose of 0.2 to 1.6 mg twice per day, where applicable; and ralinupag is used in a dose of 0.05 to 1.45 mg per day, where applicable.

[0124] Here, macitentan has an administration or administration regimen as described in any one of embodiments (a) to (k) and (n). In preferred embodiments, these doses relate to macitentan for use in the treatment and / or prophylaxis of mild or moderate PAH.

[0125] In a preferred embodiment, these combinations relate to macitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0126] (r) Further aspects of the present invention relate to a pharmaceutical composition for use in the treatment of PAH comprising macitentan and at least a pharmaceutically acceptable excipient, wherein the composition contains macitentan in an amount greater than 20 mg and less than 300 mg per day, for example, greater than 20 mg and less than 250 mg, preferably 37.5 mg, 75 mg or 150 mg, more preferably 37.5 mg or 75 mg, most preferably 75 mg.

[0127] Please understand that macitentan may have a dosage in any one of the daily doses shown in (a) to (e).

[0128] In a preferred embodiment, the pharmaceutical composition is intended for use in the treatment and / or prevention of mild or moderate PAH.

[0129] (s) Further aspects of the present invention relate to a pharmaceutical composition according to aspect (r), i) Based on the total weight of the pharmaceutical composition, macitentan is present in a total amount of 10 to 50% by weight, ii) Based on the total weight of the pharmaceutical composition, a filler consisting of lactose monohydrate containing microcrystalline cellulose in a total amount of 10 to 85% by weight, iii) Based on the total weight of the pharmaceutical composition, in a total amount of 1 to 10% by weight, starch glycol A disintegrant consisting of sodium starch glycolate, or a combination of sodium starch glycolate and polyvinylpyrrolidone, iv) A surfactant consisting of polysorbate in a total amount of 0.1 to 1% by weight based on the total weight of the pharmaceutical composition, v) A pharmaceutical composition comprising a lubricant consisting of magnesium stearate in a total amount of 0.05 to 5% by weight, based on the total weight of the pharmaceutical composition.

[0130] (t) Further aspects of the present invention relate to the pharmaceutical composition described in aspect (r) or (s), wherein the pharmaceutical composition is in the form of a capsule or a tablet (in particular, in the form of a tablet containing 75 mg of macitentan).

[0131] (u) Further aspects of the present invention relate to macitentan for use in the treatment and / or prevention of PAH as described in any one of aspects (a) to (q), where treatment and / or prevention means a reduction in the morbidity and / or mortality risk of PAH. That is, this aspect of the present invention relates to macitentan for use in reducing the morbidity and / or mortality risk of PAH, wherein macitentan is used in a manner according to any one of aspects (a) to (q).

[0132] The reduction in PAH morbidity and / or mortality risk can be evaluated as a composite morbidity / mortality risk reduction, defined, for example, as the time from baseline to the first clinical exacerbation up to 7 days after EOT (end of treatment) of the following event (primary endpoint): ●Death (all-cause mortality rate); ● Hospitalization due to pulmonary hypertension (including atrial spasm surgery, lung transplantation with or without heart transplantation, or initiation of parenteral prostacyclin due to worsening of PAH); ●The worsening of PAH led to the initiation of parenteral prostanoid therapy. ●The progression of pulmonary hypertension-related diseases is defined as follows: ● For patients with functional class II and III at baseline (both criteria must be met): ●A decrease of more than 15% in 6-minute walk distance (6MWD) from baseline was confirmed by two 6MWD trials conducted on day 2 within two weeks of each other. ● Initiation of additional PAH therapy, or worsening of WHO functional class, ● For patients with functional class IV at baseline (both criteria must be met): ●A reduction of more than 15% in 6MWD from baseline was confirmed by two 6MWD trials conducted on day 2 within two weeks of each other. ● Initiation of additional PAH therapy.

[0133] Alternatively, the reduction in the incidence and / or mortality risk of PAH may be evaluated separately.

[0134] The above evaluation may be carried out, for example, according to the following schedule. i) Run-in period (e.g., 4 weeks) with a dose of 10 mg of macitentan per day; ii) Titration period with a dose of 37.5 mg of macitentan per day (e.g., 4 weeks); iii) A maintenance period with a daily dose of 75 mg of macitentan.

[0135] The above evaluation may be performed, for example, by a double-blind study with a control group that received a dose of 10 mg of macitentan per day during the titration and maintenance periods.

[0136] To reduce the incidence and / or mortality risk of PAH, the dose of macitentan is 1 day The dose may be 60-90 mg per day. Preferably, the dose is 65-85 mg per day, more preferably 70-80 mg per day, and most preferably 75 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Doses of 65-90 mg or 65-75 mg per day are also disclosed. A further preferred dose range is 72-78 mg per day.

[0137] Furthermore, the dosage of macitentan may be 10 mg per day, followed by 25-50 mg per day, preferably 37.5 mg per day, followed by 60-90 mg per day, preferably 75 mg per day, and optionally followed by 100-200 mg per day, preferably 150 mg per day.

[0138] It should be understood that all disclosed aspects are also disclosed in the form of macitentan for the manufacture of a drug for use in any one of aspects (a) to (q) and (u).

[0139] (a') One aspect of the present invention relates to macitentan for the manufacture of a drug used for the treatment and / or prevention of pulmonary arterial hypertension (PAH) in humans, wherein the dose of macitentan is greater than 20 mg and less than 300 mg per day, for example, greater than 20 mg and less than 250 mg per day. It should be understood that the disclosure of aspect (a) applies equally.

[0140] (b') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of pulmonary arterial hypertension (PAH) according to aspect (a'), wherein PAH is mild or moderate PAH, preferably moderate PAH. It should be understood that the disclosure of aspect (b) is equally applicable.

[0141] (c') Another aspect of the present invention relates to macitentan for the manufacture of an agent used for the treatment and / or prevention of PAH as described in aspect (a') or (b'), wherein the dose is 60 to 90 mg per day, preferably 65 to 85 mg per day, more preferably 70 to 80 mg per day, and most preferably 75 mg per day. It should be understood that the disclosure of aspect (c) is also applicable.

[0142] (d') Another aspect of the present invention relates to macitentan for the manufacture of an agent used for the treatment and / or prevention of PAH according to aspect (a') or (b'), wherein the dose of macitentan is 25 to 50 mg per day, preferably 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that the disclosure of aspect (d) is equally applicable.

[0143] (e') Another aspect of the present invention relates to macitentan for the manufacture of an agent used for the treatment and / or prevention of PAH according to aspect (a') or (b'), wherein the dose of macitentan is 110 to 200 mg per day, preferably 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that the disclosure of aspect (e) is equally applicable.

[0144] (f') Another aspect of the present invention relates to macitentan for the manufacture of an agent used for the treatment and / or prevention of PAH according to aspect (a') or (b'), wherein the dose of macitentan is 60 to 90 mg twice daily, preferably 65 to 85 mg twice daily, more preferably 70 to 80 mg twice daily, and most preferably 75 mg twice daily. Aspect ( It should be understood that the disclosure in f) applies equally.

[0145] (g') Another aspect of the present invention relates to macitentan for the manufacture of an agent used for the treatment and / or prevention of PAH according to aspect (a') or (b'), wherein the dose of macitentan is 25 to 50 mg twice daily, preferably 30 to 45 mg twice daily, more preferably 35 to 40 mg twice daily, and most preferably 37.5 mg twice daily. It should be understood that the disclosure of aspect (g) is similarly applicable.

[0146] (h') Another aspect of the present invention relates to macitentan for the manufacture of an agent used for the treatment and / or prevention of PAH according to aspect (a') or (b'), in which case the dose of macitentan is gradually increased from 10 mg per day, followed by 25 to 50 mg per day, preferably 37.5 mg per day, and optionally followed by 60 to 90 mg per day, preferably 75 mg per day. It should be understood that the disclosure of aspect (h) is similarly applicable.

[0147] (i') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the dose of macitentan is gradually increased from 10 mg per day, followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that the disclosure of aspect (i) is equally applicable.

[0148] (j') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH according to aspect (h'), in which the dose of macitentan is escalated from 10 mg once daily, preferably for 15 to 45 days, followed by 25 to 50 mg once daily, preferably 37.5 mg once daily, preferably for 15 to 45 days, and optionally followed by 60 to 90 mg once daily, preferably 75 mg once daily, or 37.5 mg twice daily. It should be understood that the disclosure of aspect (j) is similarly applicable.

[0149] (k') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH according to aspect (i'), wherein the dose of macitentan is 10 mg once daily, preferably increased gradually for 15 to 45 days, followed by 60 to 90 mg per day, preferably 75 mg once daily, or 37.5 mg twice daily. It should be understood that the disclosure of aspect (k) is equally applicable.

[0150] (l') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH as described in any one of aspects (a') to (d'), wherein the dose of macitentan is 25 to 50 mg per day, preferably 37.5 mg per day, preferably increased for 15 to 45 days, and optionally followed by 60 to 90 mg per day, preferably 75 mg per day, provided that the patient is already being treated with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the disclosure of aspect (l) is equally applicable.

[0151] (m') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH as described in any one of aspects (a') to (c'), wherein the dose of macitentan is 60 to 90 mg per day, preferably 75 mg per day, under the condition that the patient is already being treated with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the disclosure of aspect (m) is equally applicable.

[0152] (n') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH as described in any one of aspects (a') to (m'), wherein macitentan is combined with a PDE5 inhibitor and / or a prostacyclin analog and / or a prostacyclin receptor agonist and / or a soluble guanylate cyclase stimulant. It should be understood that the disclosure of aspect (n) is equally applicable.

[0153] (o') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH according to aspect (n'), wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil, and udenafil; the prostacyclin analog is selected from epoprostinol, treprostinil, iloprost, and beraprost; the prostacyclin receptor agonist is selected from selexipag and larinupag; and the soluble guanylate cyclase stimulant is selected from riociguat and biriciguat. It should be understood that the disclosure of aspect (o) is equally applicable.

[0154] (p') Another aspect of the present invention relates to macitentan for the manufacture of a pharmacopoeia for use in the treatment and / or prevention of PAH according to aspect (n') or (o'), wherein macitentan is combined with tadalafil and / or selexipag or larinupag, preferably tadalafil and / or selexipag. It should be understood that the disclosure of aspect (p) is equally applicable.

[0155] (q') Another aspect of the present invention relates to macitentan for the manufacture of a drug for use in the treatment and / or prevention of PAH according to aspect (p'), wherein tadalafil is present in a dose of 20 to 40 mg per day, preferably 40 mg per day, where applicable; selexipag is present in a dose of 0.2 to 1.6 mg twice per day, where applicable; and ralinupag is present in a dose of 0.05 to 1.45 mg per day, where applicable. It should be understood that the disclosure of aspect (q) is similarly applicable.

[0156] (u') Another aspect of the present invention relates to macitentan for the manufacture of a drug for use in the treatment and / or prevention of PAH as described in any one of aspects (a') to (q'), where treatment and / or prevention means a reduction in the morbidity and / or mortality risk of PAH. That is, this aspect of the present invention relates to macitentan for the manufacture of a drug for reducing the morbidity and / or mortality risk of PAH, wherein macitentan is administered by the method of any one of aspects (a') to (q'). It should be understood that the disclosure of aspect (u) is equally applicable.

[0157] Please understand that the comments and details in aspects (a) to (q) and (u) also apply to aspects (a') to (q') and (u').

[0158] Furthermore, it should be understood that all disclosed aspects (a) to (q) and (u) should also be considered to be disclosed in the form of a treatment method.

[0159] (a) One aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) in humans, the method comprising administering macitentan to a subject in need at a dose greater than 20 mg and less than 300 mg per day, for example, greater than 20 mg and less than 250 mg / day. It should be understood that the disclosure of aspect (a) is equally applicable.

[0160] (b) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary hypertension (PAH) according to aspect (a), wherein the PAH is mild or moderate, preferably moderate PAH. It should be understood that the disclosure of aspect (b) is equally applicable.

[0161] (c) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (a) or (b), wherein the dose of macitentan is 60 to 90 mg per day, preferably 65 to 85 mg per day, more preferably 70 to 80 mg per day, and most preferably 75 mg per day. It should be understood that the disclosure of aspect (c) is equally applicable.

[0162] (d) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (a) or (b), wherein the dose of macitentan is 25 to 50 mg per day, preferably 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that the disclosure of aspect (d) is equally applicable.

[0163] (e) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (a) or (b), wherein the dose of macitentan is 110 to 200 mg per day, preferably 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that the disclosure of aspect (e) is equally applicable.

[0164] (f) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (a) or (b), wherein the dose of macitentan is 60 to 90 mg twice daily, preferably 65 to 85 mg twice daily, more preferably 70 to 80 mg twice daily, and most preferably 75 mg twice daily. It should be understood that the disclosure of aspect (f) is equally applicable.

[0165] (g) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (a) or (b), wherein the dose of macitentan is 25 to 50 mg twice daily, preferably 30 to 45 mg twice daily, more preferably 35 to 40 mg twice daily, and most preferably 37.5 mg twice daily. It should be understood that the disclosure of aspect (g) is equally applicable.

[0166] (h) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (a) or (b), wherein the dose of macitentan is gradually increased from 10 mg per day, followed by 25 to 50 mg per day, preferably 37.5 mg per day, and optionally followed by 60 to 90 mg per day, preferably 75 mg per day. It should be understood that the disclosure of aspect (h) is equally applicable.

[0167] (i) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (a) or (b), wherein the dose of macitentan is gradually increased from 10 mg per day, followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that the disclosure of aspect (i) is equally applicable.

[0168] (j) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (h), wherein the dose of macitentan is escalated from 10 mg once daily, preferably for 15 to 45 days, followed by 25 to 50 mg once daily, preferably 37.5 mg once daily, preferably for 15 to 45 days, and optionally followed by 60 to 90 mg once daily, preferably 75 mg once daily, or 37.5 mg twice daily. It should be understood that the disclosure of aspect (j) is equally applicable.

[0169] (k) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (i), wherein the dose of macitentan is 10 mg once daily, preferably increased for 15 to 45 days, followed by 60 to 90 mg per day, preferably 75 mg once daily, or 37.5 mg twice daily. It should be understood that the disclosure of aspect (k) is equally applicable.

[0170] (l) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to any one of aspects (a) to (d), wherein the dose of macitentan is 25 to 50 mg per day, preferably 37.5 mg per day, preferably increased for 15 to 45 days, and optionally followed by 60 to 90 mg per day, preferably 75 mg per day, provided that the patient is already being treated with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the disclosure of aspect (l) is equally applicable.

[0171] (m) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to any one of aspects (a) to (c), wherein the dose of macitentan is 60 to 90 mg per day, preferably 75 mg per day. The condition is that the patient is already being treated with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the disclosure of aspect (m) is equally applicable.

[0172] (n) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to any one of aspects (a) to (m), wherein macitentan is combined with a PDE5 inhibitor and / or a prostacyclin analog and / or a prostacyclin receptor agonist and / or a soluble guanylate cyclase stimulant. It should be understood that the disclosure of aspect (n) is equally applicable.

[0173] (o) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (n), wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil, and udenafil; the prostacyclin analog is selected from epoprostinol, treprostinil, iloprost, and beraprost; the prostacyclin receptor agonist is selected from selexipag and larinupag; and the soluble guanylate cyclase stimulant is selected from riociguat and biriciguat. It should be understood that the disclosure of aspect (o) is equally applicable.

[0174] (p) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (n) or (o), wherein macitentan is combined with tadalafil and / or selexipag or larinupag, preferably tadalafil and / or selexipag. It should be understood that the disclosure of aspect (p) is equally applicable.

[0175] (q) Another aspect of the present invention relates to a method for treating and / or preventing pulmonary arterial hypertension (PAH) according to aspect (p), wherein darafil is administered in a dose of 20 to 40 mg per day, preferably 40 mg per day, where applicable; selexipag is administered in a dose of 0.2 to 1.6 mg twice per day, where applicable; and larinupag is administered in a dose of 0.05 to 1.45 mg per day, where applicable. It should be understood that the disclosure of aspect (q) is similarly applicable.

[0176] (u) Another aspect of the present invention relates to a method for treating and / or preventing PAH according to any one of aspects (a) to (q), where treatment and / or prevention means a reduction in the morbidity and / or mortality risk of PAH. That is, this aspect of the present invention relates to a method for reducing the morbidity and / or mortality risk of PAH, in which macitentan is used in aspects (a) to (q). It is administered by one of the following methods. It should be understood that the disclosure of aspect (u) applies equally.

[0177] Please understand that the comments and details of aspects (a) to (q) also apply to aspects (a") to (q) and (u).

[0178] According to a further aspect of the present invention, in each of the above aspects, namely (a) to (t) and (u), (a') to (q') and (u'), and (a") to (q") and (u"), macitentan can be replaced with its active metabolite, known by the code name ACT-132577 and the international common name aprocitentan, which has the chemical formula.

[0179] [ka] This allows any weight of macitentan to be replaced with five times that weight of aprositentan.

[0180] For example, taking aspect (c) of the present invention described above, a further aspect of the present invention relates to aprocitentan for use in the treatment and / or prevention of PAH according to aspect (a) or (b), wherein the weight of macitentan aprocitentan is replaced with five times the weight of aprocitentan, and the weight of aprocitentan is 300 to 450 mg per day. Preferably, the dose of aprocitentan is 325 to 425 mg per day, more preferably 350 to 400 mg per day, and most preferably 375 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the dose of aprocitentan may also be 300 to 425 mg, 300 to 400 mg, or 300 to 375 mg per day. Doses of aprocitentan of 325–450 mg or 325–375 mg per day are also disclosed. A more preferred range is 360–390 mg of aprocitentan per day. In a more preferred embodiment, these doses of aprocitentan are administered once daily. In a preferred embodiment, these doses relate to aprocitentan for use in the treatment and / or prevention of mild or moderate PAH, preferably moderate PAH.

[0181] Furthermore, the following abbreviations are used in this specification. Abbreviation: APAH-CTD: PAH associated with connective tissue disease APAH-PoPH: PAH associated with portal pulmonary hypertension aq. aqueous solution BNP (Brain Natriuretic Peptide) BPM (beats per minute) CI cardiac index Lung diffusion capacity of DLCO (carbon monoxide) CO EDTA (Ethylenediaminetetraacetic acid) ERA endothelin receptor antagonists ET Endothelin FPAH familial PAH HR (Heart Rate) IgG (Immunoglobulin G) K2EDTA ethylenediaminetetraacetate dipotassium salt mPAP = Mean Pulmonary Pressure 6MWD (6-minute walking distance) NT-proBNP (N-terminal pro-brain natriuretic peptide) PAH (Pulmonary Artery Hypertension) PAOP is synonymous with PAWP. PAWP is synonymous with PAOP, which is pulmonary capillary wedge pressure. PAP (Pulmonary Artery Pressure) PBS phosphate-buffered saline, PD Pharmacodynamics PDE5 cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase type 5PDE5 is a PDE5 inhibitor. PH (Pulmonary Hypertension) PK (Pharmacokinetics) PVR pulmonary vascular resistance RRAP (Right Arterial Pressure, sometimes also called mRAP) RHC Right Heart Catheterization SBP (Systemic Systolic Blood Pressure) SvO2 Mixed venous oxygen saturation Tris: Tris(hydroxymethyl)aminomethane; WHO (World Health Organization) WHO FC (World Health Organization Functional Class)

[0182] Experimental section The present invention will be further explained by the following non-limiting embodiments. [Examples]

[0183] The effect of macitentan on the decrease in hemoglobin concentration Hemoglobin measurements were pooled from a Phase 3 I clinical study in healthy volunteers. ● Study AC-055~102: Investigation of PK, PD, safety, and tolerability of macitentan in male subjects (The study protocol is described in "Safety, tolerability, and pharmacokinetics of macitentan, an endothelin receptor antagonist, in an escalation multiple-dose study in healthy subjects. J.Clin.Pharmacol.(2013),53(11):1131-1138) ● Study AC-055-116: Investigation of PK, PD, safety, and tolerability of macitentan in male subjects (The study protocol is described in the following publication: Tolerability, safety, pharmacokinetics, and pharmacodynamics of macitentan, a novel endothelin receptor antagonist, in healthy Japanese male subjects. Clinical Pharmacology and Therapeutics / Japanese Journal of Clinical Pharmacology (2016), 47, 143-150) ●Study AC-055-117: PK and PD of Masitentan in male Korean subjects , investigation of safety and tolerability (the research protocol is described in the following publication: Ahn et al, pharmacokinetic-pharmacodynamic relationships of macitentan, a novel endothelin receptor antagonist, after multiple doses in healthy Korean subjects, Am.J.Cardiovasc.Drugs (2014), 14(5), 377-385)

[0184] Hemoglobin concentrations measured on the morning of day 11 of macitentan treatment and at baseline on day 1 were used for analysis. The change in hemoglobin concentration compared to baseline regressed for different dose levels of macitentan, including placebo.

[0185] An Emax curve with a baseline was fitted, and the following parameters were estimated by nonlinear regression. ●E0: Changes in hemoglobin without macitentan ●Emax: The maximum change in hemoglobin can theoretically be induced by macitentan. ●ED50: A dose that results in a 50% reduction in hemoglobin.

[0186] The following formula was used. Change in hemoglobin = E0 + ((Macitentan dose × Emax) / (Macitentan dose + ED50))

[0187] The obtained dose-response curve is shown in Figure 1.

[0188] Based on the analysis, the maximum effect of macitentan on hemoglobin reduction is approximately 1.23 g / dL, and the effect of macitentan on hemoglobin already reduces the plateau at a 10 mg dose (see Figure 1). Therefore, a clinically relevant reduction in hemoglobin is less predictable than with a 10 mg dose of macitentan in humans.

Claims

1. A drug for the treatment and / or prevention of pulmonary arterial hypertension (PAH) in humans, comprising macitentan as the active ingredient, and administered at a daily dose of 75 mg.

2. The agent for the treatment and / or prevention of PAH according to claim 1, wherein the PAH is mild or moderate PAH.

3. The agent for the treatment and / or prevention of PAH according to claim 1 or 2, wherein the macitentan is combined with a PDE5 inhibitor and / or a prostacyclin analog selected from epoprostenol, treprostinil, iloprost, and beraprost and / or a prostacyclin receptor agonist and / or a soluble guanylate cyclase stimulant.

4. The agent for the treatment and / or prevention of PAH according to claim 3, wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil, and udenafil; the prostacyclin analog is selected from epoprostenol, treprostinil, iloprost, and beraprost; the prostacyclin receptor agonist is selected from selexipag and larinupag; and the soluble guanylate cyclase stimulant is selected from riociguat and biliciguat.

5. The agent for the treatment and / or prevention of PAH according to claim 3 or 4, wherein the macitentan is combined with tadalafil and / or selexipag or larinupag.

6. The agent for the treatment and / or prevention of PAH according to claim 5, wherein tadalafil is administered in a dose of 20 to 40 mg per day, selexipag is administered in a dose of 0.2 to 1.6 mg twice per day, and ralinupag is administered in a dose of 0.05 to 1.45 mg per day, if applicable.

7. A therapeutic and / or prophylactic agent for PAH according to any one of claims 1 to 6, wherein the aforementioned treatment and / or prevention means a reduction in the incidence and / or mortality risk of PAH.

8. A pharmaceutical composition for the treatment and / or prevention of PAH, comprising macitentan as an active ingredient and at least pharmaceutically acceptable excipients, wherein the pharmaceutical composition contains 75 mg of macitentan per day.

9. The agent for the treatment and / or prevention of PAH according to claim 1, wherein the agent is administered in the form of a pharmaceutical composition containing 75 mg of macitentan.

10. The aforementioned pharmaceutical composition (i) Based on the total weight of the pharmaceutical composition, a total amount of macitentan in the form of 10 to 50% by weight, (ii) Based on the total weight of the pharmaceutical composition, a filler comprising lactose monohydrate containing microcrystalline cellulose in a total amount of 10 to 85% by weight, (iii) A disintegrant comprising sodium starch glycolate in a total amount of 1 to 10% by weight based on the total weight of the pharmaceutical composition, or a combination of sodium starch glycolate and polyvinylpyrrolidone, (iv) A surfactant consisting of polysorbate in a total amount of 0.1 to 1% by weight based on the total weight of the pharmaceutical composition, (v) The pharmaceutical composition according to claim 8, comprising a lubricant consisting of magnesium stearate in a total amount of 0.05 to 5% by weight based on the total weight of the pharmaceutical composition.

11. The pharmaceutical composition according to claim 8 or 10, in the form of a capsule or tablet.

12. The aforementioned drug, (i) Based on the total weight of the aforementioned drug, a total amount of macitentan in the form of 10 to 50% by weight, (ii) Based on the total weight of the above-mentioned drug, a filler comprising lactose monohydrate containing microcrystalline cellulose in a total amount of 10 to 85% by weight, (iii) A disintegrant consisting of sodium starch glycolate in a total amount of 1 to 10% by weight based on the total weight of the aforementioned drug, or a combination of sodium starch glycolate and polyvinylpyrrolidone, (iv) A surfactant consisting of polysorbate in a total amount of 0.1 to 1% by weight based on the total weight of the aforementioned drug, (v) The agent according to claim 9, comprising a lubricant consisting of magnesium stearate in a total amount of 0.05 to 5% by weight based on the total weight of the agent.

13. The drug according to claim 9, which is in the form of a capsule or a tablet.

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