Medicine containing pemafibrate

Abstract

The problem addressed is to provide a medicine containing pemafibrate that can be provided to a patient with renal dysfunction.　Provided is a medicine containing pemafibrate or a salt thereof or a solvate thereof as an active ingredient that is for administration to patients with renal dysfunction who require treatment by pemafibrate.

Description

Medicines containing pemafibrate

[0001] The present invention relates to a medicine containing pemafibrate.

[0002] Pemafibrate (chemical name: (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) or a salt thereof, or a solvate thereof is a compound that has a PPARα activating effect, and is known to be useful in the prevention and treatment of diseases such as dyslipidemia (Patent Document 1).

[0003] Yokote et al. have investigated the safety and efficacy of pemafibrate in patients with chronic kidney disease (Non-Patent Document 1). In this report, pemafibrate was administered at 0.2-0.4 mg / day and blood concentrations of pemafibrate were measured in patients with kidney disease. However, due to concerns that pemafibrate may cause rhabdomyolysis, it is still contraindicated, along with other fibrate drugs such as fenofibrate and bezafibrate, in patients with renal dysfunction, such as those with serum creatinine levels of 2.5 mg / dL or higher or creatinine clearance of less than 40 mL / min (Non-Patent Documents 2, 3, 4). In Yokote et al.'s report, the blood concentrations of pemafibrate after long-term administration in patients with kidney disease were not fully confirmed, and it was not clear whether blood concentrations would increase to the extent that they could cause rhabdomyolysis. Furthermore, sustained-release preparations have a higher single-dose drug dose and are absorbed over a longer period of time, so accidental overdose is more likely to result in serious side effects or poisoning than immediate-release preparations (Non-Patent Document 5). For this reason, more careful administration is required. Furthermore, rhabdomyolysis has been reported in patients with renal dysfunction who were administered other fibrates in combination with HMG-CoA reductase inhibitors (Non-Patent Document 6).

[0004] International Publication No. 2005 / 023777

[0005] Int J Mol Sci. 2019 Feb;20(3):706. Package insert "Palmodia® Tablets 0.1 mg", Kowa Company, Limited, revised May 2021 (10th edition). Package insert "Tricor® Tablets 53.3 mg / Tricor® Tablets 80 mg", Aska Pharmaceutical Co., Ltd., revised July 2023 (3rd edition). Package insert "Bezatol® SR Tablets 100 mg / Bezatol® SR Tablets 200 mg", Kissei Pharmaceutical Co., Ltd., revised March 2023 (1st edition). Yakushin No. 1 No. 5 "Guidelines for the Design and Evaluation of Sustained-Release Dosage Forms (Oral Dosage Forms)", March 11, 1988. Pharmaceutical interview form "Palmodia® Tablets 0.1 mg", Kowa Company, Limited, revised *2021 (12th edition).

[0006] An object of the present invention is to provide a medicine containing pemafibrate that can be provided to patients with renal dysfunction.

[0007] In order to achieve the above-mentioned object, the present inventors have conducted extensive research and found that even when pemafibrate is administered to patients with renal dysfunction for 12 weeks, the blood concentration does not reach a clinically problematic level, regardless of the degree of renal dysfunction or whether a statin is used concomitantly, and have completed the present invention.

[0008] That is, the present invention provides the following [Aspect 1] to [Aspect 60]. [Aspect 1] A pharmaceutical comprising pemafibrate or a salt thereof, or a solvate of these as an active ingredient, for administration to a patient with renal dysfunction who requires treatment with pemafibrate. [Aspect 2] The pharmaceutical according to Aspect 1, wherein the pharmaceutical is not administered as part of a clinical trial. [Aspect 3] The pharmaceutical according to Aspect 1 or 2, which is a sustained-release formulation. [Aspect 4] The pharmaceutical according to any of Aspects 1 to 3, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min. [Aspect 5] The pharmaceutical according to any of Aspects 1 to 4, wherein the pharmaceutical is used in combination with a statin. [Aspect 6] The pharmaceutical according to any of Aspects 1 to 4, wherein the patient has an estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m as last measured 3 days prior to treatment with pemafibrate. 2Aspect 7: The patient has an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m or less, and the patient has been receiving administration of a statin before starting treatment with pemafibrate. 2Aspect 8: The pharmaceutical according to any one of Aspects 1 to 7, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 200 mg / dL. Aspect 9: The pharmaceutical according to any one of Aspects 1 to 7, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL. Aspect 10: The pharmaceutical according to any one of Aspects 1 to 7, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL. Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, muscle hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclo [Aspect 11] The pharmaceutical according to any one of Aspects 1 to 10, wherein the patient is a patient not suffering from hyperlipidemia, ataxia, stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, hepatic failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting-induced or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.[Aspect 12] Treatment with pemafibrate improves or reduces the symptoms of hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperCKemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, and stroke. [Aspect 13] The pharmaceutical according to any one of Aspects 1 to 12, which is for the treatment of one or more of the following: Reye-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, hepatic failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. [Aspect 14] Use of pemafibrate, or a salt thereof, or a solvate thereof, for the manufacture of a medicament for administration to a patient with renal impairment who requires treatment with pemafibrate. [Aspect 15] The use according to Aspect 14, wherein the medicament is not administered as part of a clinical trial. [Aspect 16] The use according to Aspect 14 or 15, wherein the medicament is a sustained-release formulation. [Aspect 17] The use according to any of Aspects 14 to 16, wherein the patient has renal impairment with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min. [Aspect 18] The use according to any of Aspects 14 to 17, wherein the medicament is used in combination with a statin. [Aspect 19] The patient's estimated glomerular filtration rate (eGFR), last measured 3 days prior to treatment with pemafibrate, was 45 mL / min / 1.73 m. 2The use according to any one of Aspects 14 to 18, wherein the patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL / min / 1.73 m , and the patient has been receiving administration of a statin prior to the start of treatment with pemafibrate. 2Aspect 21: The use according to any one of Aspects 14 to 20, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 200 mg / dL. Aspect 22: The use according to any one of Aspects 14 to 20, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL. Aspect 23: The use according to any one of Aspects 14 to 20, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL. Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, muscle hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus The use according to any one of Aspects 14 to 22, wherein the patient is a patient not suffering from hyperlipidemia, ataxia, stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, hunger- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. [Aspect 24] The use according to any one of Aspects 14 to 23, wherein the patient is not suffering from hyperlipidemia.[Aspect 25] Treatment with pemafibrate improves or reduces the symptoms of hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, muscle hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperCKemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like syndrome, and the like. The use according to any one of Aspects 14 to 22 or 24, which is for the treatment of one or more of the following selected from symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. [Aspect 26] The use according to any one of Aspects 14 to 25, which is for the treatment of one or more of the following ... [Aspect 27] Pemafibrate or a salt thereof, or a solvate thereof for administration to a patient with renal dysfunction who requires treatment with pemafibrate. [Aspect 28] Pemafibrate or a salt thereof, or a solvate thereof according to Aspect 27, wherein the pemafibrate, the salt thereof, or a solvate thereof is not administered as part of a clinical trial. [Aspect 29] Pemafibrate or a salt thereof, or a solvate thereof according to Aspect 27 or 28, which is a sustained-release formulation. [Aspect 30] Pemafibrate or a salt thereof, or a solvate thereof according to any of Aspects 27 to 29, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min. [Aspect 31] Pemafibrate or a salt thereof, or a solvate thereof according to any of Aspects 27 to 30, wherein the pemafibrate, the salt thereof, or a solvate thereof is used in combination with a statin.Aspect 32. The patient has a last measured estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m3 three days prior to treatment with pemafibrate. 2 Aspect 33: The method of claim 32, wherein the patient has an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m or less, and the patient has been administered a statin before starting treatment with pemafibrate. 2Aspect 34: The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 33, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 200 mg / dL. Aspect 35: The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 33, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL. Aspect 36: The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 33, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL. Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperCKemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like episodes [Aspect 37] The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 36, wherein the patient is a patient not suffering from hyperlipidemia, and the ...[Aspect 38] Treatment with pemafibrate is effective in treating hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperCKemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms, intellectual disability, migraine, The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 35 or 37, which is used to treat one or more conditions selected from psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, hepatic failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. [Aspect 39] The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 38, which is administered at a daily dose of 0.1 to 0.2 mg / day as pemafibrate. [Aspect 40] A method for treating a disease requiring treatment with pemafibrate, comprising administering a therapeutically effective amount of pemafibrate, or a salt thereof, or a solvate thereof to a patient with renal dysfunction. [Aspect 41] The method for treatment according to Aspect 40, wherein pemafibrate, or a salt thereof, or a solvate thereof is not administered as part of a clinical trial. [Aspect 42] The method for treatment according to Aspect 40 or 41, wherein pemafibrate, or a salt thereof, or a solvate thereof is administered as a sustained-release formulation. [Aspect 43] The method for treatment according to any of Aspects 40 to 42, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min. [Aspect 44] The method for treatment according to any of Aspects 40 to 43, wherein pemafibrate, or a salt thereof, or a solvate thereof is used in combination with a statin.Aspect 45. The patient has a last measured estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m3 three days prior to treatment with pemafibrate. 2 A method for treating a patient having an estimated glomerular filtration rate (eGFR) of less than 30 mL / min / 1.73 m , wherein the patient has been receiving administration of a statin prior to the start of treatment with pemafibrate. 2A method of treatment according to any one of Aspects 40 to 45, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 200 mg / dL. [Aspect 47] A method of treatment according to any one of Aspects 40 to 46, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 200 mg / dL. [Aspect 48] A method of treatment according to any one of Aspects 40 to 46, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL. [Aspect 49] Diseases requiring treatment with pemafibrate include hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, and cerebrovascular disease. [Aspect 50] The method of any one of Aspects 40 to 49, wherein the patient is one or more diseases selected from the group consisting of idiopathic pulmonary edema, ataxia, stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, hunger- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. [Aspect 51] The method of any one of Aspects 40 to 49, wherein the patient is not suffering from hyperlipidemia.[Aspect 51] The disease requiring treatment with pemafibrate is hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperCKemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, cerebral atrophy, cerebrovascular disease, cerebrovascular accident ... The method for treating one or more diseases selected from stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. [Aspect 52] The method for treating one or more diseases selected from stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. [Aspect 53] The method for treating one or more diseases selected from stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, [Aspect 53] The medicament according to any one of Aspects 1 to 13, wherein pemafibrate, a salt thereof, or a solvate thereof is administered for 53 weeks or more. [Aspect 54] The use according to any one of Aspects 14 to 26, wherein pemafibrate, a salt thereof, or a solvate thereof is administered for 53 weeks or more. [Aspect 55] Pemafibrate, a salt thereof, or a solvate thereof according to any one of Aspects 27 to 39, wherein pemafibrate, a salt thereof, or a solvate thereof is administered for 53 weeks or more. [Aspect 56] The method of treatment according to any one of Aspects 40 to 52, wherein pemafibrate, a salt thereof, or a solvate thereof is administered for 53 weeks or more.[Aspect 57] The pharmaceutical agent according to any one of Aspects 1 to 13 or 53, wherein the patient is undergoing treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen. Aspect 58: The use according to any one of Aspects 14 to 26 or 54, wherein the patient is undergoing treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen. [Aspect 59] The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 39 or 55, wherein the patient is undergoing treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.Aspect 60: The method of any one of Aspects 40 to 52 or 56, wherein the patient is receiving treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.

[0009] The present invention can provide new preventive and / or therapeutic options for patients with renal dysfunction.

[0010] Figure 1 shows the relationship between eGFR and pharmacokinetic parameters (AUCτ, C Max ) relationship.

[0011] As used herein, pemafibrate refers to (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid, which has the following chemical formula (A):

[0012]

[0013] The compound can be produced, for example, according to the method described in Patent Document 1. It can also be formulated according to the method described in the literature. Furthermore, a formulation containing pemafibrate has been approved in Japan as a hyperlipidemia treatment agent, "Palmodia (registered trademark) Tablets," and these "Palmodia Tablets" can also be used.

[0014] In one embodiment of the present invention, a salt and / or solvate of pemafibrate can also be used. Salts and solvates can be prepared by conventional methods. The salt of pemafibrate is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic base salts such as ammonium salt and trialkylamine salt; mineral acid salts such as hydrochloride and sulfate; and organic acid salts such as acetate. Examples of solvates of pemafibrate or its salts include hydrates and alcohol solvates (e.g., ethanol solvates).

[0015] In one aspect of the present invention, there is provided a pharmaceutical agent comprising pemafibrate, a salt thereof, or a solvate thereof as an active ingredient, for administration to a patient with renal dysfunction who requires treatment with pemafibrate.

[0016] In one aspect of the present invention, there is provided the use of pemafibrate, or a salt thereof, or a solvate thereof, for the manufacture of a medicament for administration to a patient with impaired renal function in need of treatment with pemafibrate.

[0017] In one aspect of the present invention, there is provided pemafibrate or a salt thereof or a solvate thereof for administration to a patient with impaired renal function who is in need of treatment with pemafibrate.

[0018] In one aspect of the present invention, there is provided a method for treating a disease requiring treatment with pemafibrate, which comprises administering a therapeutically effective amount of pemafibrate, a salt thereof, or a solvate thereof to a patient suffering from renal dysfunction.

[0019] In one embodiment of the present invention, pemafibrate or a salt thereof, or a solvate thereof can be formulated into a pharmaceutical preparation in the form of a tablet, capsule, granule, powder, lotion, ointment, injection, suppository, or the like using other pharmaceutically acceptable carriers. These preparations can be produced by known methods. In one embodiment of the present invention, a pharmaceutical preparation containing pemafibrate or a salt thereof, or a solvate thereof can be administered orally or parenterally, with oral administration being preferred.

[0020] In one embodiment of the present invention, pemafibrate, a salt thereof, or a solvate thereof can be formulated as an immediate-release formulation. As used herein, an "immediate-release formulation" refers to a formulation in which the release of the active ingredient from the formulation is not specifically controlled. An example of an "immediate-release formulation" is the commercially available "Palmodia® Tablets." In one embodiment of the present invention, pemafibrate, a salt thereof, or a solvate thereof can also be formulated as a sustained-release formulation. As used herein, a "sustained-release formulation" refers to a formulation in which the release rate, release time, and release site of the active ingredient from the formulation are controlled for the purpose of reducing the number of administrations or reducing side effects. Sustained-release formulations can be manufactured by various known methods. Controlled-release formulations may be reservoir-type, matrix-type, osmotic pump-type, or ion-exchange-type. Multiple-unit formulations are also acceptable. Examples of formulation bases for controlled release include ethyl acrylate-methacrylic acid copolymers, aminoalkyl methacrylate copolymers, ethyl cellulose, carnauba wax, stearyl alcohol, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, silicone, ethylene-vinyl acetate copolymers, polylactic acid, polylactic-glycolic acid, chitin, chitosan, gelatin, collagen, albumin, phospholipids, and / or cyclodextrin, as described in Saishin Pharmaceutical Science, Hirokawa Publishing Co., Ltd., published February 25, 2006, 7th edition. Commercially available products such as "Palmodia (registered trademark) XR Tablets" may also be used.

[0021] As used herein, the term "patient in need of treatment with pemafibrate" refers to a patient suffering from one or more diseases whose symptoms may be eliminated or alleviated by administration of pemafibrate, a salt thereof, or a solvate thereof.Such diseases include, but are not limited to, eye diseases such as glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, and retinitis pigmentosa; heart diseases such as angina pectoris, cardiovascular disease, coronary artery disease, cardiomyopathy, cardiac hypertrophy, cardiac dysfunction, myocardial infarction, dilated cardiomyopathy, pulmonary hypertension, conduction disorders, and Wolff-Parkinson-White syndrome; muscle atrophy diseases (muscular dystrophies (chromosomal recessive muscular dystrophies such as Duchenne muscular dystrophy and Becker muscular dystrophy, Fukuyama muscular dystrophy, Ullrich muscular dystrophy, merosin deficiency, and integravir deficiency); Congenital muscular dystrophies such as leukemia, Walker-Warburg syndrome, limb-girdle muscular dystrophy, Miyoshi muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, etc.), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) or spinal-bulbar muscular atrophy, etc.), hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperCK blood sugar, myopathy, skeletal muscle diseases such as sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms, intellectual decline, migraine, psychiatric disorders central nervous system diseases such as dystonia and myelopathy, liver diseases such as non-alcoholic steatohepatitis, primary biliary cirrhosis and liver failure, kidney diseases such as Fanconi syndrome, tubular dysfunction, glomerular lesions and myoglobinuria, pancreatic diseases such as exocrine insufficiency, blood diseases such as sideroblastic anemia and pancytopenia, inner ear diseases such as sensorineural hearing loss, intestinal diseases such as diarrhea and constipation, skin diseases such as decreased sweating and hirsutism, endocrine gland diseases such as short stature and hypocalcemia, hypoproteinemia such as hypoalbuminemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, mental and Examples of the adverse events include one or more selected from delayed motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia (familial hypercholesterolemia (homozygous), familial hypercholesterolemia (heterozygous), high LDL-cholesterolemia, etc.), high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications (diabetic nephropathy, diabetic retinopathy, etc.), peripheral arterial disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, inflammation, and the like.As used herein, "treatment with pemafibrate" means administering pemafibrate or a salt thereof, or a solvate thereof to the above-mentioned "patient in need of treatment with pemafibrate" for the purpose of eliminating or alleviating the symptoms of one or more diseases whose symptoms may be eliminated or alleviated by administering pemafibrate or a salt thereof, or a solvate thereof.

[0022] In some embodiments, the patient is one for whom blood LDL cholesterol is not sufficiently reduced by statins or one for whom statin administration is restricted. Also included are patients for whom treatment with existing LDL-C-lowering drugs is not suitable, such as patients for whom statin administration is restricted. Here, a patient for whom blood LDL-C is not sufficiently reduced by statins refers to a patient for whom blood LDL-C is not sufficiently reduced even under statin administration. Furthermore, a patient for whom statin administration is restricted refers to a patient for whom statin administration is restricted due to contraindications such as muscle-related side effects or liver damage.

[0023] In some embodiments, the patient has hyperlipidemia, and in some embodiments, the patient's fasting serum triglyceride level prior to initiation of pemafibrate treatment may be, for example, greater than or equal to 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, or 150 mg / dL.

[0024] In another embodiment, the patient does not suffer from hyperlipidemia. Also, in some embodiments, the patient may have a fasting serum triglyceride level prior to initiation of pemafibrate treatment of, for example, less than 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, or 150 mg / dL.

[0025] In one embodiment of the present invention, a "patient with renal dysfunction" is a patient with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min. As used herein, creatinine clearance is calculated by the following formula: ((urinary creatinine (mg / dL) × urine volume per minute (mL / min)) / (serum creatinine (mg / dL)) × (1.73 / body surface area (m 2 )) is calculated.

[0026] In another embodiment, the "patient with renal dysfunction" is a patient with an estimated glomerular filtration rate (eGFR) of 60 mL / min / 1.73 m 2 Less than 45 mL / min / 1.73 m 2 less than 30 mL / min / 1.73 m 2 In particular, patients whose eGFR is less than 30 mL / min / 1.73 m 2 Patients with less than 100 mg / dL eGFR are sometimes referred to as patients with "severe renal dysfunction." In this specification, eGFR may be calculated based on serum creatinine levels or serum cystatin C levels. When eGFR is calculated based on serum creatinine levels, men should be calculated based on creatinine (mg / dL) -1.094 × Age (years) -0.287 and creatinine (mg / dL) for women. -1.094 × Age (years) -0.287 When calculating eGFR based on serum cystatin C levels, men [104 × cystatin C (mg / dL)] -1.019 ×0.996 年齢(歳) ] -8, women [104 × cystatin C (mg / dL) -1.019 ×0.996 年齢(歳) × 0.929] - 8. Whether to use a serum creatinine level or a serum cystatin C level should be determined by a person skilled in the art, taking into account the patient's condition, such as the patient's skeletal muscle mass, whether or not the patient is receiving medication such as steroids or cyclosporine, and whether or not the patient has hypothyroidism. In one embodiment, a "patient with renal dysfunction" is defined as a patient with an estimated glomerular filtration rate (eGFR) calculated based on serum creatinine levels of 60 mL / min / 1.73 m 2 Less than 45 mL / min / 1.73 m 2 less than 30 mL / min / 1.73 m 2 In particular, patients whose eGFR is less than 30 mL / min / 1.73 m 2 In another aspect, a "patient with renal dysfunction" is defined as a patient with an estimated glomerular filtration rate (eGFR) calculated based on serum cystatin C levels of 60 mL / min / 1.73 m or less. 2Less than 45 mL / min / 1.73 m 2 less than 30 mL / min / 1.73 m 2 In particular, patients whose eGFR is less than 30 mL / min / 1.73 m 2 Patients with less than this level are sometimes referred to as having "severe renal dysfunction."

[0027] In a further embodiment, the patient may be undergoing dialysis treatment.

[0028] In some embodiments, pemafibrate or a salt thereof, or a solvate thereof may be used in combination with a statin. The patient may have been administered with a statin prior to the start of pemafibrate treatment. In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m as measured last three days prior to the start of pemafibrate treatment. 2 and the patient has been receiving a statin prior to the start of treatment with pemafibrate. As used herein, "statin" refers to a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and examples include atorvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin, and salts thereof. The embodiment of the present invention using a statin includes an embodiment in which these statins are in the form of a solvate.

[0029] In some embodiments, the patient may also be receiving other therapeutic agents, including, but not limited to, anion exchange resins such as cholestyramine, colestimide, colesevelam, and salts thereof, intestinal cholesterol transporter inhibitors such as ezetimibe and salts of ezetimibe, nicotinic acid derivatives such as niacin, tocopherol nicotinate, tocopherol, niceritrol, nicomol, and salts thereof, omega-3 fatty acids and salts or esters of omega-3 fatty acids (icosapentaenoic acid, icosapentaenoic acid salts, icosapentaenoic acid esters such as ethyl icosapentaenoate, docosapentaenoic acid, niacin ... polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids such as hexaenoic acid, salts of docosahexaenoic acid, esters of docosahexaenoic acid such as ethyl docosahexaenoate, etc.; PCSK9 inhibitors such as human anti-PCSK9 (proprotein convertase subtilisin / kexin type 9) monoclonal antibodies (evolocumab, alirocumab, etc.); MTP (microsomal triglyceride transfer protein) inhibitors such as lomitapide and salts of lomitapide such as lomitapide mesylate; Apo-4-aminobenzoates such as volanesorsen and salts of volanesorsen; CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors such as anacetrapib and salts of anacetrapib, ACL (ATP citrate lyase) inhibitors such as bempedoic acid and salts of bempedoic acid, probucol and salts of probucol, and mipomersen and salts of mipomersen. This embodiment also includes an embodiment in which these other therapeutic agents are solvated.

[0030] The effective amount and frequency of administration vary depending on the patient's weight, age, sex, symptoms, etc., but can be determined appropriately by those skilled in the art. For example, for a typical adult, pemafibrate can be administered at 0.05 to 0.8 mg per day in 1 to 3 divided doses, preferably 0.1 to 0.4 mg per day in 1 to 2 divided doses, and more preferably 0.1 to 0.2 mg per day in 1 or 2 divided doses. If the eGFR is 30 mL / min / 1.73 m 2For patients with an eGFR of less than 30 mL / min, administration may be initiated at a lower dose or the administration interval may be extended. For patients with an individual eGFR of less than 30 mL / min, administration may be initiated at a lower dose or the administration interval may be extended. The maximum dose for such patients may be up to 0.2 mg per day. When a sustained-release formulation is administered to such patients, 0.2 mg may be administered once per day. In one aspect of the present invention, the administration period of pemafibrate or a salt thereof, or a solvate thereof may be appropriately set, and may be, for example, 12 weeks or more, 24 weeks or more, 36 weeks or more, 53 weeks or more, 60 weeks or more, 72 weeks or more, 96 weeks or more, or 104 weeks or more.

[0031] In one embodiment of the present invention, pemafibrate, a salt thereof, or a solvate thereof is not used in a clinical trial. As used herein, the term "clinical trial" refers to a clinical trial that has been notified to the competent authority of a country or region. In Japan, the "competent authority" is the Pharmaceuticals and Medical Devices Agency (PMDA) as of the filing date of this application.

[0032] The present invention will be described in more detail below with reference to examples, but these examples do not limit the present invention.

[0033] Example 1: Post-marketing clinical trial of pemafibrate in patients with renal impairment Objective of the study To investigate the pharmacokinetics and safety of Palmodia tablets (this drug, immediate-release tablets) 0.2 mg / day (twice daily) administered for 12 weeks to dyslipidemic patients with renal impairment and high TG (triglyceride) levels, and to verify that the degree of renal impairment does not have a clinically significant effect on the pharmacokinetics of pemafibrate, thereby obtaining information that will serve as a basis for reviewing the precautions for use. Study design: Multicenter, placebo-controlled, randomized, double-blind, parallel-group comparative study Enrollment criteria: (1) Patients with dyslipidemia aged 20 years or older at the time of consent (2) Males or postmenopausal women (3) Subjects with fasting serum TG of 150 mg / dL or higher in a screening test (4) Subjects who meet any of the following criteria: 1) eGFR of 30 mL / min / 1.73 m at the time of screening 21) Subjects with an eGFR of 30 mL / min / 1.73 m at the time of screening (Group A) 2) Subjects currently receiving hemodialysis (Group B) 2 More than 60 mL / min / 1.73 m 2 (Group C) Exclusion criteria (excerpt) (1) Patients with severe liver damage, cirrhosis, or biliary obstruction (2) Patients with gallstones (3) Pregnant women or women who may be pregnant (4) Those who are taking or need to take continuously during the study period any prohibited concomitant medication in this study (5) Those who have undergone kidney transplantation

[0034] Test method Within each of the following groups, patients were randomly assigned in a 3:1 ratio to either the Palmodia tablet group or the placebo group. Group A: 8 patients with severe renal impairment (non-dialysis patients) Group B: 4 patients with severe renal impairment (dialysis patients) Group C: 8 patients with mild to moderate renal impairment (non-dialysis patients) The treatment period was 12 weeks, and either Palmodia tablet or placebo was orally administered at a dose of 1 tablet twice a day, morning and evening, for 12 weeks. Evaluation items Pharmacokinetics Primary evaluation items Pharmacokinetic parameters of unchanged pemafibrate at 12 weeks of treatment: AUC 0- τ (area under the concentration-time curve from time 0 to the administration interval τ hours) Safety evaluation items (excerpt) Side effects, etc. Efficacy evaluation items Changes (rate or amount of change) from baseline values ​​(values ​​at week 0 of the treatment period) at each measurement time point of lipid-related test items

[0035] Main study results [Pharmacokinetics] AUC at 12 weeks 0- Regarding τ, the ratio of the geometric mean value of the severe renal impairment group to the mild to moderate renal impairment group (control group) and its 90% confidence interval are shown in the following Table 1, and no increase in exposure was observed even in the severe renal impairment group. 0- τ or C max No tendency for the maximum blood concentration to increase was observed.

[0036]

[0037] The plasma pharmacokinetic parameters were as shown in Table 2 below.

[0038]

[0039] [Safety] The incidence rates of side effects, serious side effects, and side effects leading to discontinuation of administration are shown in Table 3 below.

[0040]

[0041] Regarding side effects, one patient in the C group receiving Palmodia tablets showed a positive urine myoglobin level, leading to discontinuation of administration. No serious side effects were observed. [Efficacy] The change rate from baseline in fasting serum TG from 4 weeks into the treatment period to 4 weeks after the end of administration was as shown in Table 4 below.

[0042]

[0043] Example 2: Pemafibrate sustained-release tablets "Palmodia XR Tablets" The formulation is a film-coated tablet, a multiple-unit sustained-release formulation containing 0.2 or 0.4 mg of the active ingredient per tablet. The formulation contains the following excipients: microcrystalline cellulose (granules), hydrous silicon dioxide, hypromellose, methacrylic acid copolymer L, ethyl cellulose, magnesium stearate, D-mannitol, microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, titanium oxide, triethyl citrate, light anhydrous silicic acid, yellow ferric oxide, and carnauba wax.

[0044] Example 3: Domestic Phase II Study of Pemafibrate Extended-Release Tablets (CR-01 Study, CTD5.3.1.1-1, Study Period: September to December 2019) A 12-group, two-period crossover study was conducted in 60 patients with dyslipidemia and elevated TG levels, in which Palmodia XR Tablets (this drug, extended-release tablets) 0.4 or 0.8 mg / day, or Palmodia Tablets (existing product, immediate-release tablets) 0.2 mg / day were orally administered for 4 weeks (no washout period) (see Table 5 below). The PK (pharmacokinetic) parameters of this drug at 4 weeks after the start of administration for each dose were as shown in Table 6 below. In addition, the C of this drug when administered after a meal compared to when administered in a fasting state was max and AUC 0-24hThe geometric mean ratios [90% CI (confidence interval)] of the area under the plasma concentration-time curve from 0 to 24 hours after administration were 1.124 [0.840, 1.503] and 1.097 [0.879, 1.370], respectively, for Palmodia XR Tablets 0.4 mg / day.

[0045]

[0046]

[0047] Based on the PK data obtained in the Phase II study (CR-01 study), the AUC of this drug when administered with Palmodia Tablets 0.2 mg / day was adjusted to take into account the difference in the number of doses per day and the single dose. 0-12h AUC of this drug when administered with Palmodia XR Tablets at 0.4 mg / day and 0.8 mg / day (area under the plasma concentration-time curve from 0 to 12 hours after administration) 0-24h The geometric mean ratios [95% CI] of the CIs were calculated. The results showed that when Palmodia tablets 0.2 mg / day were compared with Palmodia XR tablets 0.4 mg / day, the AUCs were 0.863 [0.797, 0.934] and 0.870 [0.788, 0.960] when administered fasting and after a meal, respectively, and when Palmodia tablets 0.2 mg / day were compared with Palmodia XR tablets 0.8 mg / day, the AUCs were 0.879 [0.812, 0.952] and 1.035 [0.940, 1.139] when administered fasting and after a meal, respectively, and there was no significant difference in the exposure of this drug between Palmodia XR tablets and Palmodia tablets at either dose. The AUC of this drug when administered with Palmodia tablets 0.2 mg / day was 0.879 [0.812, 0.952] and 1.035 [0.940, 1.139] when administered fasting and after a meal, respectively. 0-12h Regarding the correction of AUC when Palmodia XR tablets were administered 0-24h and AUC when Palmodia tablets were administered 0-12h Both are AUCs that reflect the elimination of this drug from the blood per administration. In the CR-01 study, Palmodia XR tablets were administered once daily, whereas Palmodia tablets were administered twice daily, and the daily dose of Palmodia XR tablets was twice (4 mg / day) or four times (8 mg / day) that of Palmodia tablets (2 mg / day). Taking this into consideration, the AUC of this drug when Palmodia tablets were administered at 0.2 mg / day 0-12h was set to 4 or 8 times, respectively.

[0048] Example 4: Verification Study (ER-02 Study, CTD5.3.5.1-1, Implementation Period: March to September 2021) A randomized, double-blind, parallel-group comparative study was conducted at 11 sites in Japan to evaluate the non-inferiority of Palmodia XR Tablets (this drug, extended-release tablets) 0.2 mg / day and 0.4 mg / day to Palmodia Tablets (existing product, immediate-release tablets) 0.2 mg / day in patients with dyslipidemia and high TG levels (target number of cases: 345 (115 per group)). Subjects were dynamically assigned to one of the following groups: Palmodia XR Tablets 0.2 mg / day, Palmodia XR Tablets 0.4 mg / day, or Palmodia Tablets 0.2 mg / day, based on factors such as site, sex, timing of administration of the investigational drug (fasting or after a meal), and whether or not they were concomitantly taking a statin. After a screening period of up to 8 weeks, during the 12-week treatment period, subjects were to orally administer 0.2 or 0.4 mg of Palmodia XR tablets once daily after breakfast, or 0.1 mg of Palmodia tablets twice daily after breakfast and dinner. The investigational drug was administered at a fixed timing (fasting or after meals) throughout the study period, as directed by the principal investigator (subinvestigator). The regulations for concomitant medications were the same as those in the CR-01 study (see "Example 3: Domestic Phase II Study").

[0049] The main inclusion criteria were patients aged 20 years or older with dyslipidemia who met the following criteria: - Fasting serum TG of 200 mg / dL or higher on two consecutive occasions at screening - Fasting serum TG of 1000 mg / dL or lower at screening Of the 356 randomized patients (119 patients in the Palmodia XR Tablets 0.2 mg / day group, 119 patients in the Palmodia XR Tablets 0.4 mg / day group, and 118 patients in the Palmodia Tablets 0.2 mg / day group; the same order applies hereinafter), 355 patients (118 patients, 119 patients, and 118 patients) received the investigational drug and were included in the safety analysis population, excluding one patient in the Palmodia XR Tablets 0.2 mg / day group who requested consent withdrawal and discontinuation. Of these, 353 cases (117 cases, 119 cases, 117 cases) with at least one evaluable data point during the 4, 8, or 12 week treatment period were included in the FAS (largest analysis population), and as a result of examining the differences, Palmodia XR tablets 0.4 and 0.8 mg / day were repeatedly administered to dyslipidemic patients with high TG levels for 4 weeks.

[0050] The FAS was the primary efficacy analysis population. Six patients discontinued the study (3, 1, and 2 patients, respectively). The reasons for discontinuation were consent withdrawal / request for discontinuation (3, 1, and 0 patients, respectively) and adverse events (0, 0, and 2 patients, respectively). The primary efficacy endpoint was the percent change from baseline in TG at weeks 4, 8, and 12 of treatment. Regarding the primary endpoint, the non-inferiority of the Palmodia XR Tablets 0.4 mg / day group to the Palmodia Tablets 0.2 mg / day group was first evaluated. If non-inferiority was confirmed, the non-inferiority of the Palmodia XR Tablets 0.2 mg / day group to the Palmodia Tablets 0.2 mg / day group was then evaluated. If non-inferiority was confirmed, the point estimate of the Palmodia XR Tablets 0.4 mg / day group was confirmed to be lower than the point estimate of the Palmodia XR Tablets 0.2 mg / day group. The percent change from baseline in fasting serum TG at weeks 4, 8, and 12 of treatment was as shown in Table 7 below. The difference in the primary endpoint between the Palmodia XR Tablets 0.4 mg / day group and the Palmodia Tablets 0.2 mg / day group (least squares mean difference [95% CI]) was 0.00 [-4.79, 4.79]%, and the upper limit of the 95% CI was below the pre-specified non-inferiority limit (10%), demonstrating non-inferiority of the Palmodia XR Tablets 0.4 mg / day group to the Palmodia Tablets 0.2 mg / day group.

[0051] In addition, the difference [95% CI] between the Palmodia XR Tablet 0.2 mg / day group and the Palmodia Tablet 0.2 mg / day group for the primary endpoint was 4.20 [-0.62, 9.02]%, and the upper limit of the 95% CI was below the pre-specified non-inferiority margin (10%), demonstrating non-inferiority of the Palmodia XR Tablet 0.2 mg / day group to the Palmodia Tablet 0.2 mg / day group. Furthermore, the point estimates for the Palmodia XR Tablet 0.4 mg / day group and the Palmodia XR Tablet 0.2 mg / day group for the primary endpoint were -48.00% and -43.80%, respectively, meaning that the point estimate for the Palmodia XR Tablet 0.4 mg / day group was lower than the point estimate for the Palmodia XR Tablet 0.2 mg / day group. If values ​​from the two screening tests and at week 0 of the treatment period were available, the average of these was used as the baseline value. If only a value from week 0 of the treatment period was available, this value was used as the baseline value. In addition, the non-inferiority limit was set at 10%, based on the validation study design for Palmodia tablets.

[0052]

[0053] The secondary endpoints were the rates of change from baseline in fasting serum TC (total cholesterol), LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), and non-HDL-C (lipoprotein cholesterol other than high-density lipoprotein cholesterol) at weeks 4, 8, and 12 of the treatment period, and the results are shown in Table 8 below.

[0054]

[0055] Regarding safety, the occurrence of adverse events is as shown in Table 9 below.

[0056]

[0057] No deaths were reported.Serious adverse events other than death were reported in two patients in the Palmodia XR Tablets 0.2 mg / day group (COVID-19, COVID-19 pneumonia) and one patient in the Palmodia Tablets 0.2 mg / day group (COVID-19), but a causal relationship to the study drug was ruled out in both cases.Adverse events leading to discontinuation of study drug administration were reported in two patients in the Palmodia Tablets 0.2 mg / day group (dizziness, myalgia), and although a causal relationship to the study drug was not ruled out in both cases, the outcomes were recovery (dizziness) or relief (myalgia).

[0058] Example 5: Long-Term Administration Study (ER-03 Study, CTD5.3.5.2-1, 2, Study Period: February 2021 to June 2022) A randomized, open-label, parallel-group comparative study was conducted at 16 sites nationwide to evaluate the safety and efficacy of long-term administration of Palmodia XR tablets (main drug, extended-release tablets) in the morning or evening in patients with dyslipidemia and elevated TG levels (target number of cases: 110 (55 per group)). Subjects were dynamically assigned to either the Palmodia XR morning or evening group based on factors such as site, gender, timing of administration of the study drug (fasting or after a meal), and whether or not they were receiving a statin. After a screening period of up to 8 weeks, Palmodia XR tablets were administered orally once daily in the morning or evening during the 52-week treatment period. The starting dose was 0.2 mg / day, and if fasting serum TG reached 150 mg / dL at any point during weeks 8 to 40 of administration, the dose was increased to 0.4 mg / day after testing at the next scheduled visit (weeks 12 to 44 of administration, every 4 weeks). The principal investigator (subinvestigator) instructed each subject to maintain the same timing of administration of the investigational drug (fasting or after meals) throughout the study period. The regulations for concomitant medications were the same as those in the CR-01 study (see "Example 3: Domestic Phase II Study").

[0059] The main inclusion criteria were patients aged 20 years or older with dyslipidemia who met the following criteria: - Fasting serum TG levels of 150 mg / dL or higher on two consecutive occasions at screening - Fasting serum TG levels of 1000 mg / dL or lower at screening All 121 randomized patients (61 patients in the morning group receiving Palmodia XR tablets and 60 patients in the evening group receiving Palmodia XR tablets, respectively) received the study drug and were included in the FAS and safety analysis population. The FAS was the primary efficacy analysis population. Seven patients (2 patients, 5 patients) discontinued the study drug after administration due to adverse events (2 patients, 5 patients). The final dose of Palmodia XR tablets for the 121 patients who completed or discontinued the study was 0.2 mg / day: 39 patients (17 patients, 22 patients) and 0.4 mg / day: 82 patients (44 patients, 38 patients).

[0060] The mean percent change from baseline in fasting serum TG at the final evaluation, which was the primary endpoint of efficacy, and at the time point immediately before that, is shown in Table 10. The final evaluation was at 52 weeks of administration or at discontinuation. The mean value of the two screening tests and week 0 of the treatment period was used as the baseline value.

[0061]

[0062] The rates of change from baseline in other lipid parameters at the time of the final evaluation and the time point immediately before that are shown in Table 11. When values ​​were available from the two screening tests and at week 0 of the treatment period, the average value of these was used as the baseline value, and when only a value at week 0 of the treatment period was available, this value was used as the baseline value.

[0063]

[0064] Regarding safety, the occurrence of adverse events is as shown in Table 12 below.

[0065]

[0066] Adverse events leading to death were observed in one patient in the Palmodia XR Tablets evening administration group (myocardial infarction), but a causal relationship to the study drug was denied.Serious adverse events other than death were observed in five patients in the Palmodia XR Tablets morning administration group (carotid artery stenosis, retinal hemorrhage, colon cancer, arrhythmia, bladder cancer) and two patients in the Palmodia XR Tablets evening administration group (COVID-19, contusion), and a causal relationship to the study drug was denied except for arrhythmia.Adverse events leading to discontinuation of the study drug were observed in four patients in the Palmodia XR Tablets evening administration group (myalgia, aortic valve stenosis / asthenia / muscle pain / abnormal sensation, eczema, increased blood CK (creatine kinase)), and a causal relationship to the study drug could not be denied for any of the events.The outcomes were aortic valve stenosis not resolved, and the others recovered.

[0067] Example 6: Evaluation of rhabdomyolysis Rhabdomyolysis, an important identified risk of this drug, was evaluated. The occurrence of events related to rhabdomyolysis (rhabdomyolysis, myopathy) in the ER-02 and ER-03 studies is shown in the following Table 13, and no clear difference was observed between Palmodia XR Tablets (this drug, extended-release tablets) and Palmodia Tablets (existing product, immediate-release tablets).

[0068]

[0069] Rhabdomyolysis-related events leading to discontinuation of the study drug were observed in one patient in the Palmodia Tablets 0.2 mg / day group in Study ER-02 (myalgia) and in three patients in the Palmodia XR Tablets group in Study ER-03 (myalgia in two patients, increased blood CK (creatine phosphokinase)). A causal relationship to the study drug was not ruled out for any of these events, but they improved or recovered with no treatment or outpatient treatment. In neither clinical trial were there any clinically significant changes in laboratory values ​​related to rhabdomyolysis and renal dysfunction (blood CK, blood Cr (creatinine), and eGFR). Furthermore, the presence or absence of renal dysfunction and the concomitant use of statins in subjects who experienced events related to rhabdomyolysis in Study ER-02 and Study ER-03 are shown in Table 14 below. Although rhabdomyolysis-related events were observed in four patients with renal impairment concomitantly taking statins, they were mild (three cases) or moderate (one case), and all resolved. There was no trend toward an increased risk of rhabdomyolysis in patients with renal impairment concomitantly taking statins.

[0070]

[0071] Example 7: Therapeutic evaluation of sustained-release tablets in patients with renal dysfunction. When the administration of Palmodia XR Tablets (this drug, sustained-release tablets) and Palmodia Tablets (existing product, immediate-release tablets) to patients with renal dysfunction was investigated, the incidence of adverse events by renal function in the ER-02 and ER-03 studies was as shown in the following Table 15. 2 In the subgroup of patients with eGFR less than 30 mL / min / 1.73 m, the incidence of adverse events was similar in the Palmodia XR tablet group and the Palmodia tablet group. 2 Two patients with less than 18 months of age were enrolled, and no deaths or serious adverse events other than death were observed in these two patients.

[0072]

[0073] The present invention is useful as a medicament for preventing and / or treating a disease requiring treatment with pemafibrate.

Claims

1. A medicine comprising pemafibrate or a salt thereof, or a solvate thereof as an active ingredient, for administration to a patient with renal dysfunction who requires treatment with pemafibrate.

2. The medicament of claim 1, wherein the medicament is not administered as part of a clinical trial.

3. The pharmaceutical composition according to claim 1 or 2, which is a sustained release formulation.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min.

5. The medicine according to any one of claims 1 to 4, which is used in combination with a statin.

6. The patient has a last measured estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m3 3 days prior to treatment with pemafibrate. 2 The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient is a patient with a blood glucose level of less than 100 mg / kg, and the patient has been administered a statin before starting treatment with pemafibrate.

7. The patient's estimated glomerular filtration rate (eGFR) is 30 mL / min / 1.73 m 2 The pharmaceutical composition according to any one of claims 1 to 6, wherein the amount of 8. The pharmaceutical agent according to any one of claims 1 to 7, wherein the patient's fasting serum triglyceride level prior to the start of treatment with pemafibrate is less than 200 mg / dL.

9. The pharmaceutical agent according to any one of claims 1 to 7, wherein the patient's fasting serum triglyceride level prior to the start of treatment with pemafibrate is less than 150 mg / dL.

10. Treatment with pemafibrate has the following adverse effects: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyper-HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, The pharmaceutical composition according to any one of claims 1 to 9, which is for the treatment of one or more of the following conditions: idiopathic rheumatoid arthritis, ataxia, stroke-like symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, decreased sweating, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the patient is not suffering from hyperlipidemia.

12. Treatment with pemafibrate has the following symptoms: hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like syndrome 12. The medicament according to any one of claims 1 to 9 or 11, which is for the treatment of one or more selected from the group consisting of chronic kidney disease, idiopathic rheumatoid arthritis, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.

13. The medicine according to any one of claims 1 to 12, which is administered at 0.1 to 0.2 mg / day as pemafibrate.

14. Use of pemafibrate, or a salt thereof, or a solvate thereof, for the manufacture of a medicament for administration to a patient with impaired renal function in need of treatment with pemafibrate.

15. The use of claim 14, wherein the medicament is not administered as part of a clinical trial.

16. The use according to claim 14 or 15, wherein the medicament is a sustained release formulation.

17. The use according to any one of claims 14 to 16, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min.

18. The use according to any one of claims 14 to 17, wherein the medicament is used in combination with a statin.

19. The patient has a last measured estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m3 3 days prior to treatment with pemafibrate. 2 The use according to any one of claims 14 to 18, in a patient having an idiopathic pulmonary fibrosis of less than 5 years, wherein the patient is receiving a statin prior to initiating treatment with pemafibrate.

20. A patient has an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m 2 The use according to any one of claims 14 to 19, wherein the 21. The use according to any one of claims 14 to 20, wherein the patient has a fasting serum triglyceride level of less than 200 mg / dL prior to initiation of treatment with pemafibrate.

22. The use according to any one of claims 14 to 20, wherein the patient has a fasting serum triglyceride level of less than 150 mg / dL prior to initiation of treatment with pemafibrate.

23. Treatment with pemafibrate has been shown to improve the following: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus The use according to any one of claims 14 to 22, which is for the treatment of one or more of the following: chronic obstructive pulmonary disease, ataxia, stroke-like symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental and motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.

24. The use according to any one of claims 14 to 23, wherein the patient is not suffering from hyperlipidemia.

25. Treatment with pemafibrate has the following adverse effects: hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms 25. The use according to any one of claims 14 to 22 or 24, which is for the treatment of one or more of the following: decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome and hypoproteinemia.

26. The use according to any one of claims 14 to 25, wherein pemafibrate is administered at a dose of 0.1 to 0.2 mg / day.

27. Pemafibrate or a salt thereof, or a solvate thereof, for administration to a patient with renal impairment in need of treatment with pemafibrate.

28. The method of claim 27, wherein the pemafibrate, its salt, or its solvate is not administered as part of a clinical trial.

29. Pemafibrate or a salt thereof, or a solvate thereof according to claim 27 or 28, which is a sustained release formulation.

30. Pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 29, in which the patient has renal dysfunction with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min.

31. Pemafibrate, a salt thereof, or a solvate thereof according to any one of claims 27 to 30, wherein pemafibrate, a salt thereof, or a solvate thereof is used in combination with a statin.

32. The patient has a last measured estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m3 3 days prior to treatment with pemafibrate. 2 The method according to any one of claims 27 to 31, wherein the patient is a patient having a blood glucose level of less than 100 mg / kg, and the patient has been administered a statin before starting treatment with pemafibrate, or a salt thereof, or a solvate thereof.

33. A patient has an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m 2 The pemafibrate or its salt, or a solvate thereof according to any one of claims 27 to 32, wherein the pemafibrate or its salt or a solvate thereof is less than 100 mg / kg.

34. Pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 33, in which the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 200 mg / dL.

35. Pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 33, in which the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg / dL.

36. Treatment with pemafibrate has been shown to improve the following: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyper-HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms, The pemafibrate or its salt or solvate thereof according to any one of claims 27 to 35, which is for the treatment of one or more selected from intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, nonalcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental and motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.

37. Pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 36, wherein the patient is not suffering from hyperlipidemia.

38. Treatment with pemafibrate has been shown to improve the following: hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms, intellectual disability, migraine, and mental retardation. The pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 35 or 37, which is for the treatment of one or more selected from the group consisting of chronic kidney disease, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, hepatic failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental and motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.

39. Pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 38, which is administered at 0.1 to 0.2 mg / day as pemafibrate.

40. A method for treating a disease requiring treatment with pemafibrate, comprising administering a therapeutically effective amount of pemafibrate, a salt thereof, or a solvate thereof to a patient suffering from renal dysfunction.

41. The method of treatment according to claim 40, wherein pemafibrate or a salt thereof or a solvate thereof is not administered as part of a clinical trial.

42. The method of treatment according to claim 40 or 41, which is administered as a sustained release formulation.

43. A method for treatment according to any one of claims 40 to 42, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg / dL or more or a creatinine clearance of less than 40 mL / min.

44. The method of treatment according to any one of claims 40 to 43, wherein pemafibrate or a salt thereof, or a solvate thereof is used in combination with a statin.

45. The patient has a last measured estimated glomerular filtration rate (eGFR) of 45 mL / min / 1.73 m3 3 days prior to treatment with pemafibrate. 2 The method of any one of claims 40 to 44, wherein the patient is receiving a statin prior to the start of treatment with pemafibrate.

46. ​​A patient's estimated glomerular filtration rate (eGFR) is 30 mL / min / 1.73 m 2 The method of any one of claims 40 to 45, wherein the 47. A method of treatment according to any one of claims 40 to 46, wherein the patient has a fasting serum triglyceride level of less than 200 mg / dL prior to initiation of pemafibrate treatment.

48. A method of treatment according to any one of claims 40 to 46, wherein the patient has a fasting serum triglyceride level of less than 150 mg / dL prior to initiation of pemafibrate treatment.

49. The diseases requiring treatment with pemafibrate include hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyper-HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonic muscular atrophy ... The method for treating any one of claims 40 to 48, wherein the disease is one or more diseases selected from the group consisting of rhonus, ataxia, stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.

50. The method of treatment according to any one of claims 40 to 49, wherein the patient is not suffering from hyperlipidemia.

51. The diseases requiring treatment with pemafibrate are: hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke The method according to any one of claims 40 to 48 or 50, wherein the symptom is one or more diseases selected from the group consisting of chronic reyelia, chronic kidney disease ...

52. A method of treatment according to any one of claims 40 to 51, wherein pemafibrate is administered at a dose of 0.1 to 0.2 mg / day.

53. The pharmaceutical composition according to any one of claims 1 to 13, wherein pemafibrate or a salt thereof, or a solvate thereof is administered for 53 weeks or more.

54. The use according to any one of claims 14 to 26, wherein pemafibrate or a salt thereof, or a solvate thereof is administered for 53 weeks or more.

55. Pemafibrate, a salt thereof, or a solvate thereof according to any one of claims 27 to 39, wherein pemafibrate, a salt thereof, or a solvate thereof is administered for 53 weeks or more.

56. A method of treatment according to any one of claims 40 to 52, in which pemafibrate or a salt thereof, or a solvate thereof is administered for 53 weeks or more.

57. The medicament according to any one of claims 1 to 13 or 53, wherein the patient is receiving treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.

58. The use of any one of claims 14 to 26 or 54, wherein the patient is undergoing treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.

59. The pemafibrate or its salt or solvates thereof according to any one of claims 27 to 39 or 55, wherein the patient is undergoing treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.

60. The method of any one of claims 40 to 52 or 56, wherein the patient is receiving treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.

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