WO2023143364A1 - 一种血小板生成素受体激动剂的给药方案 - Google Patents

一种血小板生成素受体激动剂的给药方案 Download PDF

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WO2023143364A1
WO2023143364A1 PCT/CN2023/073126 CN2023073126W WO2023143364A1 WO 2023143364 A1 WO2023143364 A1 WO 2023143364A1 CN 2023073126 W CN2023073126 W CN 2023073126W WO 2023143364 A1 WO2023143364 A1 WO 2023143364A1
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patient
pharmaceutically acceptable
acceptable salt
haltrombopag
hepatic impairment
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PCT/CN2023/073126
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English (en)
French (fr)
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林宏达
沈凯
沈亚琪
胡月
丁艳华
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江苏恒瑞医药股份有限公司
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Priority to CN202380014937.1A priority Critical patent/CN118317776A/zh
Publication of WO2023143364A1 publication Critical patent/WO2023143364A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the disclosure belongs to the technical field of medicine and relates to a dosage regimen of a thrombopoietin receptor agonist.
  • Platelets are cells that play an important role in the process of stopping bleeding and repairing damaged blood vessels.
  • primary immune thrombocytopenia immunothrombocytopenia
  • bone marrow failure diseases such as aplastic anemia (aplastic anemia, AA)
  • malignant blood diseases such as myelodysplastic syndromes (myelodysplastic syndromes, MDS)
  • chronic Liver disease as well as chemotherapy, radiotherapy, bacterial or viral infection (HIV, HCV, etc.
  • ITP immune thrombocytopenia
  • AA aplastic anemia
  • MDS myelodysplastic syndromes
  • chronic Liver disease as well as chemotherapy, radiotherapy, bacterial or viral infection (HIV, HCV, etc.
  • thrombocytopenia The main hazard of thrombocytopenia is hemorrhage or increased risk of hemorrhage, which can lead to visceral or even intracranial hemorrhage in severe cases, endangering the life of the patient; or restricting clinical surgical treatment. Therefore, rapidly, effectively and safely increasing the platelet count of patients with thrombocytopenic diseases is one of the current clinical research hotspots. Studies have found that thrombopoietin receptor agonist (thrombopoietin receptor agonist, TPORA) is of great significance in the treatment of thrombocytopenia caused by various causes.
  • TPORA thrombopoietin receptor agonist
  • liver disease is an important site for drug biotransformation and drug elimination. Reports in many biomedical literatures have demonstrated that liver disease can alter drug absorption and disposition (PK), as well as its efficacy and safety (PD). Changes in drug metabolism and excretion activities caused by liver function damage may lead to drug accumulation, or in a few cases the inability to form active metabolites, thereby affecting the effectiveness and safety of the drug.
  • Liver injury is a condition in which the normal function of the liver is reduced. Liver injury can be acute, paroxysmal, or chronic. Chronic liver damage or cirrhosis can result from a variety of causes, such as excessive alcohol consumption, hepatitis, autoimmune disease, genetics or metabolism, or can be sudden.
  • Liver damage is usually irreversible, and treatment consists of preventing disease progression and treating symptoms. In severe cases, liver transplantation is the only option. Liver injury that does not manifest overt symptoms or is characterized by symptoms such as decreased ability of blood to clot (coagulopathy) and brain dysfunction (encephalopathy), hydroperitoneal fluid, increased risk of infection, hypogonadism, changes in liver size , jaundice, and increased sensitivity to drugs.
  • coagulopathy coagulopathy
  • encephalopathy brain dysfunction
  • hydroperitoneal fluid hydroperitoneal fluid
  • increased risk of infection hypogonadism
  • changes in liver size jaundice
  • jaundice and increased sensitivity to drugs.
  • liver function index that can effectively predict drug PK and PD clinically.
  • clinical studies in patients with impaired hepatic function can provide information to help determine the starting dose for these patients.
  • the present disclosure provides a ((Z)-5-(2-hydroxyl-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetra Hydronaphthalene-2-yl)-1H-
  • a compound of pyrazole-4(5H-ylidene)hydrazino)phenyl)furan-2-carboxylic acid) or a pharmaceutically acceptable salt thereof, namely haitrombopag or a pharmaceutically acceptable salt thereof, can be used as a platelet-forming TPO receptor agonists can increase the content of platelets in the blood and are used to treat various blood diseases, such as diseases caused by platelet defects.
  • thrombocytopenia such as primary immune thrombocytopenia (immune thrombocytopenia, ITP), bone marrow failure diseases such as aplastic anemia (aplastic anemia, AA), malignant blood diseases such as myelodysplastic syndrome (myelodysplastic syndromes, MDS), chronic liver disease, and patients with thrombocytopenia caused by chemotherapy, radiotherapy, bacterial or viral infection (HIV, HCV, etc.).
  • primary immune thrombocytopenia ITP
  • bone marrow failure diseases such as aplastic anemia (aplastic anemia, AA)
  • malignant blood diseases such as myelodysplastic syndrome (myelodysplastic syndromes, MDS)
  • chronic liver disease and patients with thrombocytopenia caused by chemotherapy, radiotherapy, bacterial or viral infection (HIV, HCV, etc.
  • the present disclosure provides a method of administering haltrombopag, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient has mild liver impairment, the method comprising:
  • a therapeutically effective amount of haltrombopag or a pharmaceutically acceptable salt thereof to said patient with mild hepatic impairment, wherein the initial dose of haltrombopag or a pharmaceutically acceptable salt thereof is compared to normal hepatic function
  • the initial dose administered to the patient was not adjusted.
  • the present disclosure also provides haltrombopag, or a pharmaceutically acceptable salt thereof, for use in a method of treating thrombocytopenia in a patient in need thereof, wherein the patient has mild liver impairment, the method comprising: administering Said patient with mild hepatic impairment is administered a therapeutically effective amount of haltrombopag or a pharmaceutically acceptable salt thereof, wherein the initial dose of haltrombopag or a pharmaceutically acceptable salt thereof is compared to that administered to a patient with normal liver function The initial dose was not adjusted.
  • the present disclosure also provides a use of haltrombopag or a pharmaceutically acceptable salt thereof for the treatment of thrombocytopenia, wherein the patient suffers from mild liver damage, and the administration of the therapeutically effective amount of haitrombopag or a pharmaceutically acceptable salt thereof, wherein the initial dose of haitrombopag or a pharmaceutically acceptable salt thereof is not adjusted compared to the initial dose administered to patients with normal liver function.
  • a method of administering haitrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild liver damage comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof with An amount equivalent to 2.5-15 mg of haltrombopag was administered to the patient with mild hepatic impairment.
  • a method of administering haitrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild liver damage comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof with An amount equivalent to 2.5 mg of haltrombopag was administered to the patient with mild hepatic impairment.
  • a method of administering haitrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild liver damage comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof with An amount equivalent to 5 mg of haltrombopag was administered to the patient with mild hepatic impairment.
  • a method of administering haitrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild liver damage comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof with An amount equivalent to 7.5 mg of haltrombopag was administered to the patient with mild hepatic impairment.
  • a method of administering haitrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild liver damage comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof with An amount equivalent to 10 mg of haltrombopag was administered to the patient with mild hepatic impairment.
  • a method of administering haitrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild liver damage comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof with An amount equivalent to 15 mg of haltrombopag was administered to the patient with mild hepatic impairment.
  • the present disclosure provides a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient has moderate hepatic impairment, the method comprising:
  • the present disclosure also provides haltrombopag, or a pharmaceutically acceptable salt thereof, for use in a method of treating thrombocytopenia in a patient in need thereof, wherein the patient has moderate hepatic impairment, the method comprising:
  • the present disclosure also provides a use of haltrombopag or a pharmaceutically acceptable salt thereof for the treatment of thrombocytopenia, wherein the patient suffers from moderate liver damage, and a therapeutically effective amount of Haitrombopag or a pharmaceutically acceptable salt thereof, wherein the initial dose of haltrombopag or a pharmaceutically acceptable salt thereof is less than the initial dose administered to patients with normal liver function or mild liver function impairment.
  • the method comprises administering to said patient with moderate hepatic impairment an initial dose of said haltrombopag or a pharmaceutically acceptable salt thereof that is greater than that administered to a patient with normal or mild hepatic impairment.
  • the initial dose administered is 10%-90% less.
  • the method comprises administering to said patient with moderate hepatic impairment an initial dose of said haltrombopag or a pharmaceutically acceptable salt thereof that is greater than that of normal hepatic function or mild hepatic impairment. Patients are administered 20%-80% less initial dose.
  • the method comprises administering to said patient with moderate hepatic impairment said haltrombopag or
  • the initial dose of its pharmaceutically acceptable salt is 30%-70% less than the initial dose administered to patients with normal liver function or mild liver function impairment.
  • the method comprises administering to said patient with moderate hepatic impairment an initial dose of said haltrombopag or a pharmaceutically acceptable salt thereof that is greater than that of normal hepatic function or mild hepatic impairment. Patients are administered 40%-60% less initial dose.
  • the method comprises administering to said patient with moderate hepatic impairment an initial dose of said haltrombopag or a pharmaceutically acceptable salt thereof that is greater than that of normal hepatic function or mild hepatic impairment. Patients were administered 50% less of the initial dose.
  • the method comprises administering to said patient with moderate hepatic impairment an initial dose of said haltrombopag or a pharmaceutically acceptable salt thereof that is greater than that of normal hepatic function or mild hepatic impairment.
  • the initial dose administered by the patient is reduced by 1 mg-5 mg.
  • the method comprises administering to said patient with moderate hepatic impairment an initial dose of said haltrombopag or a pharmaceutically acceptable salt thereof that is greater than that of normal hepatic function or mild hepatic impairment.
  • the initial dose administered by the patient was reduced by 2.5 mg.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from moderate hepatic impairment comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof at an equivalent Haitrombopag was administered to the patient with moderate hepatic impairment in an amount of 2.5-15 mg.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from moderate hepatic impairment comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof at an equivalent Haitrombopag was administered to the patient with moderate hepatic impairment in an amount of 2.5 mg.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from moderate hepatic impairment comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof at an equivalent
  • the patient with moderate hepatic impairment was administered in an amount of 5 mg of haltrombopag.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from moderate hepatic impairment comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof at an equivalent Haitrombopag was administered to the patient with moderate hepatic impairment in an amount of 7.5 mg.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from moderate hepatic impairment comprising: administering the haitrombopag or a pharmaceutically acceptable salt thereof at an equivalent Haitrombopag was administered to the patient with moderate hepatic impairment in an amount of 10 mg.
  • the present disclosure also provides a method of administering haitrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, compared to administration of the haitrombopag or a pharmaceutically acceptable salt thereof to a patient with normal liver function.
  • Administration of tripopopag or its pharmaceutically acceptable salts at the same dose to patients with mild, moderate, and severe hepatic impairment resulted in higher exposures.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild hepatic impairment comprising: administering to the patient suffering from mild hepatic impairment a therapeutically effective An amount of said haitrombopag or a pharmaceutically acceptable salt thereof, wherein the AUC 0- ⁇ of haitrombopag administered to patients with mild liver impairment increases by 10 to 50 compared to patients with normal liver function %; preferably 15%-30% increase in Heltrebopag AUC 0- ⁇ ; more preferably 20-25% increase in Heltrebopag AUC 0- ⁇ .
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild hepatic impairment comprising: administering to the patient suffering from mild hepatic impairment a therapeutically effective An amount of said haitrombopag or a pharmaceutically acceptable salt thereof, wherein 100% to 125% of the AUC 0- ⁇ of haitrobopag administered to patients with mild hepatic impairment compared to patients with normal liver function % range.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from mild hepatic impairment comprising: administering to the patient suffering from mild hepatic impairment a therapeutically effective an amount of said haitrombopag or a pharmaceutically acceptable salt thereof, wherein administration of haitrombopag to a patient with mild liver impairment results in a 10%-100% increase in Cmax compared to a patient with normal liver function;
  • the Cmax of haltrombopag is increased by 30%-100%; more preferably, the Cmax of haltrombopag is increased by 50%-100%; most preferably, the Cmax of haltrombopag is increased by 60%-80%.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from moderate hepatic impairment comprising: administering to the patient suffering from moderate hepatic impairment a therapeutically effective amount of The haltrombopag or a pharmaceutically acceptable salt thereof, wherein the AUC 0- ⁇ of haltrombopag administered to patients with moderate hepatic impairment increases by 30%-130% compared to patients with normal liver function;
  • the AUC 0- ⁇ of haltrombopag is increased by 30%-100%; more preferably, the AUC 0- ⁇ of haltrombopag is increased by 50%-100%; most preferably, the AUC 0- ⁇ of haltrombopag is increased by 60%-80%.
  • a method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffers from moderate hepatic impairment comprising: administering to the patient suffering from moderate hepatic impairment a therapeutically effective amount of Said haltrombopag or a pharmaceutically acceptable salt thereof, wherein compared with patients with normal liver function, administration of haltrombopag to patients with mild liver damage results in a 50%-150% increase in Cmax ; preferably haltrombopag A 70%-150% increase in Tripopag C max ; more preferably a 70%-130% increase in Heltrebopag C max ; most preferably a 90%-110% increase in Heltrebopag C max .
  • the method further comprises determining whether the patient has mild, moderate or severe hepatic impairment.
  • the haitrombopag or a pharmaceutically acceptable salt thereof is haitrombopag diethanolamine salt.
  • the haltrombopag, or a pharmaceutically acceptable salt thereof is administered orally.
  • the dose of haltrombopag or a pharmaceutically acceptable salt thereof is 1-30 mg.
  • the dosage described therein is the weight of haitrombopag in a single administration of haitrombopag or a pharmaceutically acceptable salt thereof.
  • the dosage is preferably 1.0 mg, 2.0 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg.
  • the administration frequency of haltrombopag or a pharmaceutically acceptable salt thereof is once a day, twice a day or three times a day; preferably once a day.
  • Patients described in this disclosure are human patients, including adult patients and pediatric patients.
  • the patient described in the present disclosure is in need of administering the haltrombopag or a pharmaceutically acceptable salt thereof to achieve and maintain a platelet count > 50 ⁇ 10 9 /L.
  • the method of administering haltrombopag or a pharmaceutically acceptable salt thereof to a patient in need described in the present disclosure may specifically be administering haltrombopag or a pharmaceutically acceptable salt thereof for the treatment of thrombocytopenia in a patient in need
  • haltrombopag or a pharmaceutically acceptable salt thereof described in the present disclosure is administered in the form of a pharmaceutical composition.
  • compositions described in the present disclosure comprise a therapeutically effective amount of haltrombopag, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present disclosure comprises haltrombopag or a pharmaceutically acceptable salt thereof.
  • the weight of haltrombopag is selected from 1.0mg, 2.0mg, 2.5mg, 5mg, 7.5mg, 10mg , 12.5mg, 15mg, 20mg, 25mg, 30mg.
  • Heltrombopag or a pharmaceutically acceptable salt thereof, or a composition thereof can be prepared according to patent applications WO2009092276, WO2010142137, WO2017124983, and WO2020151728, and their respective disclosures are incorporated herein by reference in their entirety.
  • thrombocytopenia includes but not limited to primary immune thrombocytopenia (immune thrombocytopenia, ITP), bone marrow failure diseases such as aplastic anemia (aplastic anemia, AA), malignant blood diseases such as myeloid hyperplasia Myelodysplastic syndromes (MDS), chronic liver disease, and thrombocytopenia caused by chemotherapy, radiotherapy, bacterial or viral infection (HIV, HCV, etc.).
  • ITP primary immune thrombocytopenia
  • aplastic anemia aplastic anemia
  • MDS myeloid hyperplasia Myelodysplastic syndromes
  • chronic liver disease thrombocytopenia caused by chemotherapy, radiotherapy, bacterial or viral infection (HIV, HCV, etc.
  • tautomers of heltrebopag described in the present disclosure, although the structural formula of heltrombopag is drawn as some isomer forms for the sake of simplicity, but the present disclosure can include all isomers, such as tautomers Isomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.
  • the tautomers of hatrombopag also fall within the protection scope of the present disclosure, for example:
  • Modulate administration means to gradually decrease, lower or increase the dose of a substance, stop administering a substance to a patient, or use a different dose.
  • the active agent replaces the substance.
  • liver injury refers to hepatocellular (liver) dysfunction.
  • the "Child-Pugh score” is a score based on five clinical measures of liver injury, including levels of total bilirubin, serum albumin, PT INR, ascites, and hepatic encephalopathy. Each measure is assigned a grade of 1, 2, or 3, and the sum of the five grades is the Child-Pugh score.
  • the Child-Pugh score can be used to classify liver damage by placing subjects in Child-Pugh groups.
  • liver damage refers to a grade of liver damage level based on a Child-Pugh score of 5-6.
  • “moderate liver impairment” refers to a grade of liver impairment level based on a Child-Pugh score of 7-9.
  • liver injury refers to a grade of liver injury level based on the Child-Pugh score of 10-15.
  • Child Pugh classification mild: grade A, 5-6 points; moderate: grade B, 7-9 points; severe: grade C, 10-15 points.
  • Grade 1 restlessness, sleep disturbance, irritability/agitation, tremor, scribbled handwriting, EEG 5cps waveform;
  • Grade 2 Drowsiness, impaired time perception, abnormal behavior, asterixis, ataxia, slow triphasic EEG;
  • Grade 3 drowsiness, drowsiness, disorientation, hyperreflexia, rigidity, EEG slow wave;
  • Grade 4 Coma cannot be awakened, no personality/action, no brain reflex, slow 2-3cps delta wave activity in EEG.
  • AUC refers to the area under the curve or integral of the plasma concentration of an active pharmaceutical ingredient or metabolite over time after a dosing event.
  • AUC0 -t is the integral under the curve of the plasma concentration from time 0 (dose) to time "t".
  • AUC 0- ⁇ is the AUC from time 0 (dose) to time infinity. Unless otherwise stated, AUC refers to AUC0- ⁇ .
  • the drug is packaged in the form of a salt, such as Haitrombopag diethanolamine salt, and the dosage form strength or dosage refers to the equivalent mass of this corresponding free base (Haltrombopag).
  • Cmax is a pharmacokinetic parameter that refers to the maximum observed plasma concentration of an active pharmaceutical ingredient following delivery. C max occurs at the time t max of maximum plasma concentration.
  • the AUC or C max described in the present disclosure can be obtained through conventional experimental detection in the field, or can refer to the description in the examples.
  • Numerical values stated in this disclosure are calculated or extrapolated values, subject to some error, are meant to be ⁇ 20% of the stated value, and more specifically include ⁇ 10%, ⁇ 5%, ⁇ 2% and ⁇ 1% of the stated value.
  • administering to a patient refers to the process of introducing a compound or a pharmaceutically acceptable salt, composition or dosage form thereof into a patient by means of introduction recognized in the art.
  • an “effective amount” and “therapeutically effective amount” of an agent, compound, drug, composition, or combination, as described in the present disclosure is one that is nontoxic and effective when administered to a subject or patient (eg, a human subject or patient). amount to produce some desired therapeutic effect.
  • the precise therapeutically effective amount for a subject may depend, for example, on the subject's size and health, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinical practitioner.
  • the dose between the initial dose (Initial Dose) and the therapeutically effective dose is not completely the same, and the treatment has The dose may be the initial dose, or the dose after monitoring and dose adjustment, specifically, the adjusted dose after platelet count or metabolism monitoring.
  • Example 1 Study on Pharmacokinetics and Safety of Experimental Drugs in Mild Hepatic Impairment (Child-Pugh: Class A), Moderate Hepatic Impairment (Child-Pugh: Class B) and Normal Hepatic Function Subjects
  • Test drug Diethanolamine salt tablets of Haitrombopag, produced and provided by Jiangsu Hengrui, specifications: 2.5mg/tablet and 5mg/tablet.
  • Body mass index (BMI weight (kg)/height2 (m2)): 18-30kg/m2 (including critical value);
  • the average daily alcohol intake in the 3 months before screening exceeds the following standards: women exceed 15g (for example, 145mL wine, 497mL beer or 43mL low-alcohol liquor), men exceed 25g (for example, 290mL wine, 994mL beer or 86mL low-alcohol liquor);
  • TPO receptor agonists such as Eltrombopag, Romigrastim
  • TPIAO TPIAO within 1 month before screening
  • Female subjects are breast-feeding or have positive serum pregnancy results during the screening period or during the test;
  • the estimated glomerular filtration rate (eGFR) calculated by the modification of diet in renal disease (MDRD) formula is ⁇ 60ml/min/1.73m2;
  • malignant tumors or a history of malignant tumors within 5 years before screening (excluding skin non-melanomas that have been treated and have no signs of recurrence, and cervical intraepithelial neoplasia that has been resected);
  • Subjects with normal liver function those who have participated in any clinical trials of drugs or medical devices within 3 months before screening; subjects with liver damage: those who have participated in clinical trials of any drugs or medical devices within 1 month before screening experimenter;
  • Subjects with normal liver function who are positive for hepatitis B surface antigen, hepatitis C antibody or hepatitis C core antigen, HIV antibody or syphilis antibody;
  • liver failure subjects or liver cirrhosis subjects with hepatic encephalopathy, hepatocellular carcinoma, rupture and bleeding of esophageal and gastric varices and other complications that the investigators consider inappropriate to participate in the study;
  • HIV antibody screening is positive; if the syphilis antibody is positive, the rapid plasma reagin test (RPR) test should be added. If RPR is positive at the same time, it needs to be excluded.
  • RPR rapid plasma reagin test
  • This study was a single-dose, open-label study to evaluate the pharmacokinetics of haltrombopag in subjects with normal hepatic function, mild hepatic impairment, and subjects with moderate hepatic impairment. There are three groups in total, and the specific groups are shown in Table 1 below.
  • the degree of liver function damage of the subjects was evaluated (mild: grade A, 5 or 6 points; moderate: grade B, 7-9 points).
  • the mean weight of group C is within the range of ⁇ 10kg (including the critical value) of the mean weight of all subjects with liver damage;
  • the mean age of group C is within the mean age of all subjects with liver damage ⁇ 10 years old (including the cut-off value);
  • the number of subjects of each sex in Group C was similar to all subjects with liver impairment ( ⁇ 1 subject/sex);
  • Group A and Group B are not matched in terms of age, gender, and weight.
  • Subjects in each group will collect PK, PD and safety indicators according to the test flow chart after receiving the study drug on D1, and will conduct comparative analysis between groups.
  • PK blood sample collection time points each subject collected veins within 1 hour before administration, and at 0.5, 1, 2, 4, 6, 7, 8, 10, 12, 24, 48, 72, 96 and 120 hours after administration The blood is about 4ml.
  • Blood collection time window within 60 minutes before administration, within 0.5h-2h after administration, ⁇ 2min, 4h-12h, ⁇ 5min, and 24h-120h after administration, ⁇ 15min.
  • D-1 Before the first day of administration (D-1), the subject fasted for more than 10 hours without food and water, and in the next morning (D1) took about 240ml of warm water on an empty stomach orally orally 7.5mg of Heltrombopag diethanolamine tablets (1 for each of 2.5mg and 5mg) Tablets), withhold water within 1 hour before and after administration, eat lunch about 4 hours after administration, and eat dinner about 10 hours after administration. Keep sitting within 2 hours after administration, and subjects avoid strenuous exercise and prolonged bed rest.
  • liver damage Table 4 shows the comparative analysis results of the PK parameters of heltrebopag and subjects with normal liver function.
  • T max is expressed as Median (Min ⁇ Max)
  • t 1/2 is expressed as Mean ⁇ SD
  • others are expressed as GeoMean (%CVb).
  • Subjects with normal liver function, mild liver damage (Child-Pugh: A grade) and moderate liver damage (Child-Pugh: B grade) were given a single oral administration of 7.5 mg hetrombopag diethanolamine tablets on an empty stomach.
  • the median values are 8.00h, 2.00h and At 2.00h
  • the geometric means of C max were 36.8ng/mL, 62.4ng/mL, and 82.8ng/mL
  • the geometric means of AUC 0-t were 874h*ng/mL, 1060h*ng/mL, and 1580h*ng/mL, respectively.
  • the geometric mean values of AUC 0- ⁇ were 929h*ng/mL, 1120h*ng/mL and 1660h*ng/mL, and the arithmetic mean values of t 1/2 were 34.6h, 32.3h and 36.3h, respectively.
  • Subjects with normal liver function and subjects with mild or moderate hepatic impairment were safe and well tolerated after a single oral administration of haltrombopag, and the incidence of adverse reactions increased as the degree of hepatic impairment aggravated.
  • the severity of all drug-related AEs in this study was graded according to CTCAE5.0, and 1 case (12.5%) of grade 3 only occurred in the moderate liver injury group, including decreased white blood cell count, decreased lymphocyte count, decreased platelet count, Decreased neutrophil count; grade 2 in 7 cases (29.2%), including 1 case (12.5%) of normal liver function group with hypertriglyceridemia, and 1 case (12.5%) of mild liver injury group with neutrophil count decreased, 5 cases (62.5%) in the moderate liver injury group, including decreased white blood cell count, decreased platelet count, decreased neutrophil count, and anemia; 9 cases (37.5%) of grade 1, including 1 case (25.0%) in the normal liver function group ), 3 cases (37.5%) in the mild liver injury group, and 5 cases (62.5%) in the moderate liver injury group.

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Abstract

本公开涉及一种血小板生成素受体激动剂的给药方案。具体而言，本公开涉及一种向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤或中度肝损伤。

Description

一种血小板生成素受体激动剂的给药方案 技术领域
本公开属于医药技术领域，涉及一种血小板生成素受体激动剂的给药方案。
背景技术
血小板是在止血和受损血管的修复过程中发挥重要作用的细胞。临床上，原发免疫性血小板减少症(immune thrombocytopenia，ITP)，骨髓衰竭性疾病如再生障碍性贫血(aplastic anemia，AA)，恶性血液病如骨髓增生异常综合征(myelodysplastic syndromes，MDS)，慢性肝病，以及由化疗、放疗、细菌或病毒感染(HIV、HCV等)均可引起患者血小板减少。血小板减少最主要的危害是出血或出血风险增高，严重时可导致内脏甚至颅内出血，危及患者生命；或者限制临床手术治疗。因此，快速、有效、安全地提高血小板减少性疾病患者的血小板计数，是目前临床研究的热点之一。研究发现，血小板生成素受体激动剂(thrombopoietin receptor agonist，TPORA)在各种原因导致的血小板减少症治疗中均具有重要意义。
肝脏是药物进行生物转化和药物消除的重要部位。许多生物医学文献中的报道已经证实，肝脏疾病可以改变药物吸收和处置(PK)，也可以改变其有效性和安全性(PD)。肝功能损害引起的药物代谢和排泄活动的改变，可能导致药物蓄积，或在少数情况下无法形成活性代谢产物，进而影响药物的有效性和安全性。肝损伤是其中肝脏的正常功能降低的病况。肝损伤可以是急性的、发速发作的或慢性的。慢性肝损伤或肝硬化可以由多种原因引起，例如过度饮酒、肝炎、自身免疫性疾病、遗传或新陈代谢、或者可以是突发性的。肝损伤通常是不可逆的，治疗包括预防疾病进展和治疗症状。在严重的情况下，肝移植是唯一的选择。肝损伤不会表现出明显的症状，或由这类症状表征：如血液凝结能力下降(凝血病)和脑功能障碍(脑病)、腹腔积水、感染风险增加、性腺功能减退症、肝脏尺寸改变、黄疸和对药物的敏感性增加。
患有肝损伤的患者中的药代动力学参数(如药物的AUC、Cmax、t1/2)和/或其代谢物的变化会导致许多问题，包括需要调整剂量、医师开处方的复杂化、需要肝功能检查、缺乏正确剂量的可用性、对患有肝损伤的患者缺乏某些药物的可用性以及过量。
总的来说，临床上尚没有有效地预测药物PK和PD的肝功能指标。但是，在药物开发期间，在肝功能受损患者中进行的临床研究可提供一些信息，有助于确定这些患者的起始剂量。
本公开提供了一种式I所示((Z)-5-(2-羟基-3-(2-(3-甲基-5-氧代-1-(5,6,7,8-四氢萘-2-基)-1H- 吡唑-4(5H)-亚基)肼基)苯基)呋喃-2-羧酸)的化合物或其可药用盐，即为海曲泊帕或其可药用盐，可作为血小板生成素(TPO)受体激动剂，提高血液中血小板的含量，用于治疗多种血液疾病，如由血小板缺陷引起的疾病。同时也可以用于治疗血小板减少症，例如原发免疫性血小板减少症(immune thrombocytopenia，ITP)，骨髓衰竭性疾病如再生障碍性贫血(aplastic anemia，AA)，恶性血液病如骨髓增生异常综合征(myelodysplastic syndromes，MDS)，慢性肝病，以及由化疗、放疗、细菌或病毒感染(HIV、HCV等)均引起的患者血小板减少。
发明内容
本公开提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：
向患有轻度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量相比于向肝功能正常患者施用的初始剂量不做调节。
本公开还提供用于治疗有需要的患者中的血小板减少症的方法中的海曲泊帕或其可药用盐，其中所述患者患有轻度肝损伤，所述方法包括：向患有轻度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量相比于向肝功能正常患者施用的初始剂量不做调节。
本公开还提供一种海曲泊帕或其可药用盐用于治疗血小板减少症的用途，其中所述患者患有轻度肝损伤，向患有轻度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量相比于向肝功能正常患者施用的初始剂量不做调节。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于2.5-15mg的海曲泊帕的量施用至患有轻度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于2.5mg的海曲泊帕的量施用至患有轻度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于5mg的海曲泊帕的量施用至患有轻度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于7.5mg的海曲泊帕的量施用至患有轻度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于10mg的海曲泊帕的量施用至患有轻度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于15mg的海曲泊帕的量施用至患有轻度肝损伤的所述患者。
本公开提供一种向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：
向患有中度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量小于向肝功能正常或轻度肝功能损伤的患者施用的初始剂量。
本公开还提供用于治疗有需要的患者中的血小板减少症的方法中的海曲泊帕或其可药用盐，其中所述患者患有中度肝损伤，所述方法包括：
向患有中度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量小于向肝功能正常或轻度肝功能损伤的患者施用的初始剂量。
本公开还提供一种海曲泊帕或其可药用盐用于治疗血小板减少症的用途，其中所述患者患有中度肝损伤，向患有中度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量小于向肝功能正常或轻度肝功能损伤的患者施用的初始剂量。
在一些实施方案中，所述方法包括向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少10％-90％。
在另一些实施方案中，所述方法包括向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少20％-80％。
在另一些实施方案中，所述方法包括向患有中度肝损伤的所述患者施用的所述海曲泊帕或 其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少30％-70％。
在另一些实施方案中，所述方法包括向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少40％-60％。
在另一些实施方案中，所述方法包括向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少50％。
在另一些实施方案中，所述方法包括向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量减少1mg-5mg。
在另一些实施方案中，所述方法包括向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量减少2.5mg。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于2.5-15mg的海曲泊帕的量施用至患有中度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于2.5mg的海曲泊帕的量施用至患有中度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于5mg的海曲泊帕的量施用至患有中度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于7.5mg的海曲泊帕的量施用至患有中度肝损伤的所述患者。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：将所述海曲泊帕或其可药用盐以等同于10mg的海曲泊帕的量施用至患有中度肝损伤的所述患者。
本公开还提供向有需要的患者施用海曲泊帕或其可药用盐的方法，相比于所述海曲泊帕或其可药用盐向具有正常肝功能的患者施用，所述海曲泊帕或其可药用盐向患有轻度、中度、重度肝损伤的患者施用相同剂量将导致更高的暴露。
在某些实施方案中，其中所述暴露通过Cmax或AUC0-∞测量。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：向患有轻度肝损伤的所述患者施用治疗有效量的所述海曲泊帕或其可药用盐，其中相比于正常肝功能患者，向患有轻度肝损伤的患者所施用海曲泊帕产生的AUC0-∞增加了10～50％；优选海曲泊帕AUC0-∞增加15％-30％；更优选海曲泊帕AUC0-∞增加20-25％。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：向患有轻度肝损伤的所述患者施用治疗有效量的所述海曲泊帕或其可药用盐，其中相比于正常肝功能患者，向患有轻度肝损伤的患者所施用海曲泊帕产生的AUC0-∞的100％～125％范围之内。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：向患有轻度肝损伤的所述患者施用治疗有效量的所述海曲泊帕或其可药用盐，其中相比于正常肝功能患者，向患有轻度肝损伤的患者所施用海曲泊帕产生的Cmax增加10％-100％；优选海曲泊帕Cmax增加30％-100％；更优选海曲泊帕Cmax增加50％-100％；最优选海曲泊帕Cmax增加60％-80％。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：向患有中度肝损伤的所述患者施用治疗有效量的所述海曲泊帕或其可药用盐，其中相比于正常肝功能患者，向患有中度肝损伤的患者所施用海曲泊帕产生的AUC0-∞增加了30％-130％；优选海曲泊帕AUC0-∞增加30％-100％；更优选海曲泊帕AUC0-∞增加50％-100％；最优选海曲泊帕AUC0-∞增加60％-80％。
提供向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：向患有中度肝损伤的所述患者施用治疗有效量的所述海曲泊帕或其可药用盐，其中相比于正常肝功能患者，向患有轻度肝损伤的患者所施用海曲泊帕产生的Cmax增加50％-150％；优选海曲泊帕Cmax增加70％-150％；更优选海曲泊帕Cmax增加70％-130％；最优选海曲泊帕Cmax增加90％-110％。
在某些实施方案中，所述方法还包括确定所述患者是否患有轻度、中度或重度肝损伤。
在某些实施方案中，所述海曲泊帕或其可药用盐为海曲泊帕二乙醇胺盐。
在某些实施方案中，所述海曲泊帕或其可药用盐经口服施用。
在某些实施方案中，其中海曲泊帕或其可药用盐给药剂量为1-30mg。其中所述的给药剂量为单次给药海曲泊帕或其可药用盐中海曲泊帕的重量。给药剂量优选1.0mg、2.0mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、20mg、25mg、30mg。
在某些实施方案中，其中海曲泊帕或其可药用盐给药频次为每日一次、每次两次或每日三次；优选每日一次。
本公开中所述的患者为人类患者，包括成人患者和儿童患者。
本公开中所述的患者为需要施用所述海曲泊帕或其可药用盐达到并维持血小板计数≥50×109/L。
本公开中所述的向有需要的患者施用海曲泊帕或其可药用盐的方法，具体可为施用海曲泊帕或其可药用盐用于治疗有需要的患者中的血小板减少的方法，所述血小板减少选自由原发免疫性血小板减少症、再生障碍性贫血、重型再生障碍性贫血、慢性肝病或化疗引起患者血小板减少。
在某些实施方案中，本公开所述的海曲泊帕或其可药用盐以药物组合物的形式给药。
在某些实施方案中，本公开所述的组合物包括治疗有效量的海曲泊帕或其可药用盐和药学上可接受的载体。
在某些实施方案中，本公开所述的药物组合物中包含海曲泊帕或其可药用盐中海曲泊帕的重量选自1.0mg、2.0mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、20mg、25mg、30mg。
可以根据专利申请WO2009092276、WO2010142137、WO2017124983、WO2020151728制备海曲泊帕或其可药用盐、或其组合物等，其各自的公开内容引用整体并入文本。
本公开中所述的“血小板减少”包括但不限于原发免疫性血小板减少症(immune thrombocytopenia，ITP)，骨髓衰竭性疾病如再生障碍性贫血(aplastic anemia，AA)，恶性血液病如骨髓增生异常综合征(myelodysplastic syndromes，MDS)，慢性肝病，以及由化疗、放疗、细菌或病毒感染(HIV、HCV等)引起的血小板减少。
本公开中所述的海曲泊帕存在互变异构体，虽然为简便起见将海曲泊帕结构式画成某些异构体形式，但是本公开可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。海曲泊帕的互变异构体也属于本公开保护范围之内，例如：

本公开所述的“调节施用”、“改变施用”、“调节剂量”或“改变剂量”均是等同的并且意指逐渐减少、降低或增加物质的剂量、停止向患者施用物质或用不同的活性剂替代该物质。
本说明书通篇内对“一个实施方案”或“实施方案”或“一些实施方案”或“某个实施方案”的提及意指关于实施方案所描述的具体特征、结构或特点包含于至少一个实施方案中。因此，短语“在一个实施方案中”或“在实施方案中”或“在一些实施方案中”或“在某个实施方案中”在本说明书通篇内各个地方的出现不一定全部指代相同的实施方案。另外，具体特征、结构或特点可以在一个或多个实施方案中以任何适合的方式组合。
本公开所述，“肝损伤”是指肝细胞(肝)功能障碍。
本公开所述，“Child-Pugh评分”是基于肝损伤的五种临床测量的评分，包括总胆红素、血清白蛋白、PT INR、腹水和肝性脑病的水平。每种测量的等级分别为1、2或3，五种等级的总和为Child-Pugh评分。通过将受试者置于Child-Pugh组中，Child-Pugh评分可用于对肝损伤进行分类。
本公开所述，“轻度肝损伤”是指基于5-6的Child-Pugh评分的肝损伤水平等级。
本公开所述，“中度肝损伤”是指基于7-9的Child-Pugh评分的肝损伤水平等级。
本公开所述，“重度肝损伤”是指基于10-15的Child-Pugh评分的肝损伤水平等级。
本公开所述，“肝损伤”与“肝功能不全”的定义相同，均参考下述Child-Pugh评分标准。

Child Pugh分级：轻度：A级，5-6分；中度：B级，7-9分；重度：C级，10-15分。
*：肝性脑病分级：
0级：意识、人格、神经系统检查、脑电图均正常；
1级：躁动，睡眠障碍，易怒/激动，震颤，笔迹潦草，脑电图5cps波形；
2级：嗜睡，时间感知障碍，行为异常，扑翼样震颤，共济失调，脑电图缓慢的三相波；
3级：欲睡，昏睡，定向障碍，反射亢进，强直，脑电图慢波；
4级：昏迷无法唤醒，没有人格/行动，无大脑反射，脑电图缓慢的2－3cpsδ波活动。
#：将血清总胆红素(mg/dL)和血清白蛋白(g/dL)的单位分别换算为μmol/L和g/L，换算系数分别是17.1和10。
本公开所述，“AUC”指给药事件后，随时间推移，活性药物成分或代谢物的血浆浓度的曲线下面积或积分。
本公开所述，“AUC0-t”是从时间0(给药)至时间“t”的血浆浓度曲线下积分。
本公开所述，“AUC0-∞”是从时间0(给药)至时间无穷的AUC。除非另外声明，否则AUC指AUC0-∞。例如，药物以盐形式包装，例如海曲泊帕二乙醇胺盐，剂型规格或剂量指这种相应游离碱(海曲泊帕)的当量质量。
本公开所述，Cmax是药代动力学参数，其指递送活性药物成分后观察到的最大血浆浓度。Cmax出现在最大血浆浓度的时间tmax时。
本公开所述的AUC或Cmax可通过本领域常规实验检测获得，或可参照实施例中记载。
本公开所述的数值为计算或推断数值，存在一定误差，指所述值的±20％、并且更具体地包括所述值的±10％、±5％、±2％和±1％。
本公开所述，“向患者施用”指通过本领域公认的引入手段，将化合物或其可药用盐、组合物或剂型引入患者的过程。
本公开所述，药剂、化合物、药物、组合物或组合的“有效量”和“治疗有效量”是施用至受试者或患者(例如，人类受试者或患者)时无毒并有效用于产生某些所需治疗效果的量。受试者的精确治疗有效量可以取决于例如受试者的体格和健康、病况的性质和程度、选择用于施用的治疗剂或治疗剂的组合以及本领域技术人员已知的其他变量。给定情况的有效量通过常规实验确定并且在临床医务人员的判断内。
在本公开中，所述的初始剂量(Initial Dose)与治疗有效量间剂量并不完全相同，治疗有 效量所述剂量可以是初始剂量，也或可以是监测和剂量调整后的剂量，具体可为经血小板数量或代谢监测后的调节剂量。
具体实施方式
实施例1：试验药在轻度肝损伤(Child-Pugh：A级)、中度肝损伤(Child-Pugh：B级)和肝功能正常受试者中的药代动力学和安全性的研究
1、试验药物
试验药：海曲泊帕的二乙醇胺盐片剂，由江苏恒瑞生产并提供，规格：2.5mg/片和5mg/片。
2、入组标准
受试者必须满足以下所有入选标准才可入组本研究
1.试验前签署知情同意书、并对试验内容、过程及可能出现的不良反应充分了解；并能够按照试验方案要求完成研究；
2.受试者(包括伴侣)愿意自筛选至最后一次研究药物给药后6个月内自愿采取有效避孕措施，具体避孕措施见附录1；
3.年龄在18～65岁(包括临界值)，男女均可；
4.体重指数(BMI＝体重(kg)/身高2(m2))：18-30kg/m2(包括临界值)；
5.肝功能正常的受试者，临床实验室检查(血常规、血生化、尿常规、凝血功能)正常或异常无临床意义；
6.肝功能正常的受试者，既往无重要脏器的严重原发性疾病，包括但不限于胃肠道、呼吸系统、肾、肝、神经、血液、内分泌、肿瘤、免疫、精神或心脑血管疾病。
肝损伤的受试者，还需符合以下入选标准：
7.筛选前4周内未用药，或对肝功能损害和/或其他合并疾病需要长期治疗的有至少4周的稳定用药；
8.既往原发性肝脏疾病(药物性肝损害除外)导致的Child-Pugh分级为A级或B级的肝脏功能不全患者。
3、排除标准
如果受试者满足下列任意一项标准，将不能进入本研究：
1.筛选前3个月内平均每日吸烟大于5支；
2.过敏体质，或对海曲泊帕二乙醇胺片中的任何成份过敏；
3.筛选前3个月内平均每日摄入的酒精量超过如下标准：女性超过15g(例如，145mL葡萄酒、497mL啤酒或43mL低度白酒)，男性超过25g(例如，290mL葡萄酒、994mL啤酒或86mL低度白酒)；
4.筛选期前3个月内有药物滥用史；
5.筛选前3个月内献血或失血≥400mL，或接受输血者；
6.筛选前6个月内接受过重大手术或者手术切口没有完全愈合；
7.有深静脉血栓形成或者其他血栓栓塞事件病史或临床症状提示易栓症；
8.筛选前1个月内使用过TPO受体激动剂(如艾曲波帕、罗米司亭)或特比澳的受试者；
9.在服用研究药物前14天内服用了中草药或任何影响海曲泊帕PK的药物(见附录2药物相互作用评估)；
10.高血压【收缩压(SBP)≥160mmHg和(或)舒张压(DBP)≥100mmHg，经复查一次确认】；
11.女性受试者在筛选期或试验过程中正处在哺乳期或血清妊娠结果阳性；
12.12-ECG异常有临床意义者(如需药物治疗的心动过速/过缓、II-III度房室传导阻滞或QTcF间期延长(男性≥470ms，女性≥480ms)(按Fridericia’s公式校正)或临床医生判定有其它临床意义的异常)；
13.应用肾脏病饮食调整(modification of diet in renal disease，MDRD)公式计算的估计肾小球滤过率(estimated glomerular filtration rate，eGFR)＜60ml/min/1.73m2；
14.患有恶性肿瘤，或筛选前5年内有恶性肿瘤病史(已进行治疗且无复发征象的皮肤非黑色素瘤，和已切除的宫颈上皮内瘤变除外)；
15.肝功能正常的受试者：筛选前3个月内参加过任何药物或医疗器械的临床试验者；肝损伤的受试者：筛选前1个月内参加过任何药物或医疗器械的临床试验者；
16.肝功能正常的受试者，乙肝表面抗原、丙肝抗体或丙肝核心抗原、HIV抗体或梅毒抗体任一指标筛查呈阳性者；
17.预估试验期间可能有手术或住院倾向者；
18.给药前1天内进食过任何含有酒精(或酒精呼气试验阳性)、葡萄柚汁/西柚汁、含有甲基黄嘌呤(如咖啡、茶、可乐、巧克力、功能饮料)的食物或饮料，剧烈运动及其他影响药物吸收、分布、代谢、排泄等因素者；
19.尿药筛阳性者(吗啡、大麻)；
20.研究者认为具有任何不宜参加此试验因素者。
肝损伤的受试者补充排除标准(符合其中1条即排除)：
21.有肝移植史；
22.肝衰竭受试者，或合并肝性脑病、肝细胞癌、食管胃底静脉曲张破裂出血等研究者认为不合适参与研究的并发症的肝硬化受试者；
23.除肝脏原发疾病本身外，有任何严重疾病史，或研究者认为可能影响试验结果的病史或和/异常有临床意义临床实验室检查，包括但不仅限于循环系统、内分泌系统、神经系统、消化系统、泌尿系统或血液、免疫、精神及代谢疾病病史。
24.HIV抗体筛查呈阳性者；若梅毒抗体阳性需增加快速血浆反应素试验(RPR)检测，如RPR同时阳性，需排除。
4、试验流程
本研究是在肝功能正常的受试者、轻度肝损伤和中度肝损伤受试者中评价海曲泊帕的药代动力学的单剂量、开放设计的试验。共三组，具体分组见下表1。
表1 受试者分组
根据Child-Pugh分级来评价受试者肝功能损害的程度(轻度：A级，5或者6分；中度：B级，7-9分)。
本研究将先纳入A组和B组受试者，两组纳入均完成后，再纳入肝功能正常的受试者(C组)与所有肝损伤受试者匹配。研究人群的匹配标准描述如下：
·C组的体重均值在所有肝损伤受试者体重均值±10kg范围内(包括临界值)；
·C组的年龄均值在所有肝损伤受试者年龄均值±10岁范围内(包括临界值)；
·C组每个性别的受试者人数与所有肝损伤受试者相似(±1例受试者/性别)；
·A组与B组年龄、性别、体重不进行匹配。
各组受试者在D1接受研究用药后都将按照试验流程表进行PK、PD和安全性指标采集，并将进行组间比较分析。
5、采血时间点
PK血样采集时间点：每位受试者在给药前1h内，给药后0.5、1、2、4、6、7、8、10、12、24、48、72、96和120h采静脉血约4ml。采血时间窗：给药前60min内，给药后0.5h～2h为±2min，4h～12h为±5min，给药后24h～120h为±15min。
6、受试者给药方法
受试者第一天给药前(D-1)禁食不禁水10h以上，次日晨(D1)用约240ml温水空腹口服海曲泊帕二乙醇胺片7.5mg(2.5mg和5mg规格各1片)，给药前后1h内禁水，给药约4h后进食午餐，约10小时进食晚餐。给药后2h内保持坐位，受试者避免剧烈运动及长时间卧床。
7、药代动力学参数的计算
采用Phoenix WinNonlin 8.1以非房室模型(NCA)按实际采样时间点计算海曲泊帕药代动力学参数，包括Tmax、Cmax、AUC0-t、AUC0-∞、t1/2、V/F和CL/F。药代动力学参数的定义和计算方法见下表2。
表2 药代动力学参数定义和计算方法
8、药代动力学参数分析
轻度肝损伤(Child-Pugh：A级)、中度肝损伤(Child-Pugh：B级)和肝功能正常受试者海曲泊帕主要PK参数的描述性统计汇总结果见表3，肝损伤和肝功能正常受试者海曲泊帕PK参数对比分析结果见表4。
表3 海曲泊帕PK参数汇总(PKPS)
注：除Tmax以Median(Min～Max表示)，t1/2表示为Mean±SD，其他表示为GeoMean(％CVb)。
表4 肝损伤和肝功能正常受试者海曲泊帕PK参数对比分析(PKPS)
肝功能正常、轻度肝损伤(Child-Pugh：A级)和中度肝损伤(Child-Pugh：B级)受试者分别单次空腹口服7.5mg海曲泊帕二乙醇胺片后，Tmax的中位值分别为8.00h、2.00h和 2.00h，Cmax几何均值分别为36.8ng/mL、62.4ng/mL和82.8ng/mL，AUC0-t几何均值分别为874h*ng/mL、1060h*ng/mL和1580h*ng/mL，AUC0-∞几何均值分别为929h*ng/mL、1120h*ng/mL和1660h*ng/mL，t1/2算术均值分别为34.6h、32.3h和36.3h。
方差分析(ANOVA)结果显示，轻度肝损伤受试者与肝功能正常受试者相比较，Cmax、AUC0-t和AUC0-∞的最小二乘几何均数比值(轻度/正常)及其90％置信区间分别为170.39％(106.63％,272.27％)、121.73％(69.04％,214.63％)和120.16％(67.25％,214.70％)。中度肝损伤受试者与肝功能正常受试者相比较，Cmax、AUC0-t和AUC0-∞的最小二乘几何均数比值(中度/正常)及其90％置信区间分别为204.72％(123.49％,339.38％)、171.21％(93.26％,314.30％)和173.06％(92.66％,323.22％)。
轻度肝损伤受试者与肝功能正常受试者相比较，Cmax增加70.39％，AUC0-t增加21.73％，AUC0-∞增加20.16％。中度肝损伤受试者与肝功能正常受试者相比较，Cmax增加104.72％，AUC0-t增加71.21％，AUC0-∞增加73.06％。各个组的半衰期基本一致，肝损伤组相较于肝功能正常组的受试者中位达峰时间提前。
9、结论
轻度肝损伤受试者与肝功能正常受试者相比较，Cmax增加70.39％，AUC0-t增加21.73％，AUC0-∞增加20.16％。中度肝损伤受试者与肝功能正常受试者相比较，Cmax增加104.72％，AUC0-t增加71.21％，AUC0-∞增加73.06％。
肝损伤对海曲泊帕的血浆蛋白结合率无明显影响。
给药后各个组均能观察到血小板较基线升高的趋势且未观察到明显差异。
肝功能正常受试者和轻、中度肝损伤受试者单次口服海曲泊帕后安全性和耐受性良好，随着肝功能受损程度加重，不良反应发生率也随之升高。
本研究共入组24例受试者，所有受试者均被纳入安全分析集。研究结果显示三个组别(肝功能正常组、轻度肝损伤组、中度肝损伤组)受试者单次服用海曲泊帕乙醇胺片7.5mg后的安全性和耐受性良好，无非预期不良反应，无SAE报告，无受试者因AE提前退出试验。
本试验中发生不良事件的受试者共15例(29例次，发生率62.5％)，其中与研究药物相关的AE的受试者共有13例(25例次，发生率54.2％)，其中肝功能正常组2例(2例次，发生率25.0％)、轻度肝损伤组4例(5例次，发生率50.0％)、中度肝损伤组7例(18例次，发生率87.5％)。随着肝功能受损程度加重，不良反应发生率也随之升高。
本研究中所有与药物相关的AE严重程度均按CTCAE5.0分级，其中，3级1例(12.5％)仅发生在中度肝损伤组，为白细胞计数降低，淋巴细胞计数降低、血小板计数降低、中性粒细胞计数降低；2级7例(29.2％)，其中肝功能正常组1例(12.5％)高甘油三酯血症，轻度肝损伤组1例(12.5％)中性粒细胞计数降低，中度肝损伤组5例(62.5％)，包括白细胞计数降低，血小板计数降低、中性粒细胞计数降低、贫血；1级9例(37.5％)，包括肝功能正常组1例(25.0％)，轻度肝损伤组3例(37.5％)，中度肝损伤组5例(62.5％)。所有不良反应主要发生在肝损伤组，且中度肝损伤组的不良反应发生率相对较高，考虑受试者受基础肝病严重程度不同的影响，且绝大多数实验室检查的基线结果即为异常。所有不良事件未采取措施处理即恢复。
基于本研究中海曲泊帕在肝损伤和肝功能正常受试者中的药代动力学结果，建议轻度肝损伤患者与肝功能正常受试者起始剂量保持一致，中度肝损伤患者起始剂量降低一半，并在治疗过程中对受试者进行密切监测。

Claims (14)

  1. 向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有轻度肝损伤，所述方法包括：
    向患有轻度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量相比于向肝功能正常患者施用的初始剂量不做调节。
  2. 向有需要的患者施用海曲泊帕或其可药用盐的方法，其中所述患者患有中度肝损伤，所述方法包括：
    向患有中度肝损伤的所述患者施用治疗有效量的海曲泊帕或其可药用盐，其中所述海曲泊帕或其可药用盐的初始剂量小于向肝功能正常或轻度肝功能损伤的患者施用的初始剂量。
  3. 如权利要求2所述的方法，其中，
    向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少10％-90％；
    优选向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少20％-80％；
    更优选向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少30％-70％；
    最优选向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少40％-60％。
  4. 如权利要求2所述的方法，其中，向患有中度肝损伤的所述患者施用的所述海曲泊帕或其可药用盐的初始剂量比向肝功能正常或轻度肝功能损伤的患者施用的初始剂量少50％。
  5. 向有需要的患者施用海曲泊帕或其可药用盐的方法，其中，相比于正常肝功能的患者，所述海曲泊帕或其可药用盐向患有轻度、中度、重度肝损伤的患者施用相同剂量将导致更高的暴露。
  6. 如权利要求5所述的方法，其中所述暴露通过Cmax或AUC0-∞测量。
  7. 如权利要求5-6中任一项所述的方法，其中肝损伤
    向患有轻度肝损伤的所述患者施用治疗有效量的所述海曲泊帕或其可药用盐，其中相比于正常肝功能患者，向患有轻度肝损伤的患者所施用海曲泊帕产生的AUC0-∞增加了10～50％；
    优选海曲泊帕AUC0-∞增加15％-30％；
    更优选海曲泊帕AUC0-∞增加20-25％。
  8. 如权利要求5-6中任一项所述的方法，其中肝损伤：
    向患有中度肝损伤的所述患者施用治疗有效量的所述海曲泊帕或其可药用盐，其中相比于正常肝功能患者，向患有中度肝损伤的患者所施用海曲泊帕产生的AUC0-∞增加了30％-130％；
    优选海曲泊帕AUC0-∞增加30％-100％；
    更优选海曲泊帕AUC0-∞增加50％-100％。
  9. 如权利要求1-8中任一项所述的方法，其中所述患者为需要施用所述海曲泊帕或其可药用盐达到并维持血小板计数≥50×109/L。
  10. 如权利要求1-8中任一项所述的方法，其中所述海曲泊帕或其可药用盐施用至所述患者以治疗血小板减少症，优选所述血小板减少症选自由原发免疫性血小板减少症、再生障碍性贫血、重型再生障碍性贫血、慢性肝病或化疗引起患者血小板减少。
  11. 根据权利要求1-10中任一项所述的方法，其中所述海曲泊帕或其可药用盐为海曲泊帕二乙醇胺盐。
  12. 根据权利要求1-11中任一项所述的方法，其中海曲泊帕或其可药用盐给药剂量为1-30mg，优选2.5mg、3.75mg、5mg、7.5mg、10mg、12.5mg、15mg。
  13. 根据权利要求1-12中任一项所述的方法，其中所述的海曲泊帕或其可药用盐以药物组合物的形式给药。
  14. 根据权利要求13所述的方法，其中所述的组合物包括治疗有效量的海曲泊帕或其可药用盐和药学上可接受的载体。
PCT/CN2023/073126 2022-01-25 2023-01-19 一种血小板生成素受体激动剂的给药方案 WO2023143364A1 (zh)

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