WO2022228551A1 - 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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WO2022228551A1
WO2022228551A1 PCT/CN2022/090302 CN2022090302W WO2022228551A1 WO 2022228551 A1 WO2022228551 A1 WO 2022228551A1 CN 2022090302 W CN2022090302 W CN 2022090302W WO 2022228551 A1 WO2022228551 A1 WO 2022228551A1
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pharmaceutically acceptable
acceptable salt
formula
rosuvastatin
therapeutically effective
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PCT/CN2022/090302
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English (en)
French (fr)
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林宏达
沈凯
丁雪鹰
瞿文君
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江苏恒瑞医药股份有限公司
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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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present 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 hemostasis and the repair of damaged blood vessels.
  • ITP primary immune thrombocytopenia
  • bone marrow failure diseases such as aplastic anemia (AA)
  • AA aplastic anemia
  • MDS myelodysplastic syndromes
  • HCV bacterial or viral infection
  • the main hazard of thrombocytopenia is bleeding or increased bleeding risk, which can lead to visceral or even intracranial hemorrhage in severe cases, endangering the patient's life; or limit clinical surgical treatment.
  • thrombopoietin receptor agonist TORA
  • Eltrombopag is an oral small molecule TPORA developed by GSK.
  • the small molecule TPORA acts on the transmembrane region of TPO-R, activates the signaling pathway of human TPO-R, and leads to the proliferation and differentiation of megakaryocytes in bone marrow stem cells.
  • small molecule TPORA can stimulate hematopoietic stem cells and promote the resuscitation of bone marrow aplastic anemia for the treatment of refractory aplastic anemia.
  • the currently approved treatment indications for Eltrombopag include: (1) chronic primary immune thrombocytopenia (ITP) in adults and children (over 1 year old) who have not responded well to glucocorticoids, immunoglobulins or splenectomy,
  • ITP chronic primary immune thrombocytopenia
  • the adult indication was approved by the U.S. FDA in November 2008, and was approved in Europe in 2009, and the pediatric indication was approved by the U.S.
  • the present disclosure provides a formula ((Z)-5-(2-hydroxy-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetra Hydronaphthalene-2-yl)-1H-pyrazole-4(5H)-ylidene)hydrazino)phenyl)furan-2-carboxylic acid) compound or its pharmaceutically acceptable salt, which can be used as thrombopoietin (TPO ) receptor agonists, which increase the content of platelets in the blood and are used to treat various blood diseases, such as those caused by platelet defects.
  • TPO thrombopoietin
  • thrombocytopenia such as primary immune thrombocytopenia (ITP), bone marrow failure diseases such as aplastic anemia (AA), and hematological malignancies such as myelodysplastic syndromes (myelodysplastic syndromes, MDS), chronic liver disease, and thrombocytopenia in patients caused by chemotherapy, radiotherapy, bacterial or viral infections (HIV, HCV, etc.).
  • ITP primary immune thrombocytopenia
  • AA bone marrow failure diseases
  • AA aplastic anemia
  • hematological malignancies such as myelodysplastic syndromes (myelodysplastic syndromes, MDS), chronic liver disease, and thrombocytopenia in patients caused by chemotherapy, radiotherapy, bacterial or viral infections (HIV, HCV, etc.).
  • the main clinical indicator of the effective rate of treatment of ITP is the proportion of responders (defined as platelet count ⁇ 50 ⁇ 109/L) after 8 weeks of treatment.
  • the primary clinical endpoint was 58.9% (2.5mg group) or 64.3% (5.0mg group); according to the clinical trial results published in NCT01762761, Eltrombopag reached the primary clinical endpoint in 57.7% (60/104 25mg) patients, formula I or its pharmaceutically acceptable salt was comparable to eltrombopag in terms of therapeutic effect, with a slightly higher proportion of patients achieving the primary clinical endpoint.
  • formula I or a pharmaceutically acceptable salt thereof is an inhibitor and substrate of breast cancer resistance protein (BCRP), an efflux transporter that transports drugs from the liver to bile, while It also limits the absorption and utilization of intestinal drugs, and statins such as rosuvastatin, atorvastatin, fluvastatin and simvastatin are all BCRP substrates.
  • BCRP breast cancer resistance protein
  • statins such as rosuvastatin, atorvastatin, fluvastatin and simvastatin are all BCRP substrates.
  • Rosuvastatin known as a "super statin”
  • Rosuvastatin can effectively lower blood lipids, reverse atherosclerotic plaque, reduce inflammatory markers of atherosclerosis, and reduce the incidence of cardiovascular events in high-risk and low-risk patients and mortality, as adjunctive therapy with dietary control and other lipid-lowering measures (eg, LDL depletion therapy), with longer duration of medication.
  • rosuvastatin Compared with other statins, rosuvastatin has the advantages of high liver selectivity, low lipophilicity, and low adverse reactions.
  • the common adverse reactions are muscle toxicity, which can cause rhabdomyolysis in severe cases. Indirectly related to pharmacokinetic interactions with other drugs co-administered with statins.
  • BCRP is important for the drug disposition of rosuvastatin, and in rosuvastatin-treated subjects, BCRP(421CA) homozygotes or BCRP(421AA) homozygotes were compared with BCRP(421CC) controls. There was a two-fold difference in exposure after suvastatin. Therefore, administration of Formula I or a pharmaceutically acceptable salt thereof may increase exposure to the BCRP substrate rosuvastatin.
  • the present disclosure provides a treatment method of formula I or a pharmaceutically acceptable salt thereof, when formula I or a pharmaceutically acceptable salt thereof and a BCRP substrate are taken at the same time, drug-drug interactions of clinical significance will not occur, and the drug-drug interaction with single Cmax , AUC 0-t , AUC 0- of rosuvastatin in plasma after combined medication (rosuvastatin calcium tablet + formula I or its pharmaceutically acceptable salt) compared with medication (rosuvastatin calcium tablet)
  • the geometric least squares mean ratio of ⁇ and its 90% confidence interval are 112.87% (101.95%-124.96%), 110.28% (103.93%-117.01%), and 110.28% (103.67%-117.32%), respectively.
  • the present disclosure provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, a therapeutically effective amount of the compound represented by formula I or Its pharmaceutically acceptable salts and therapeutically effective amounts of BCRP substrates do not produce drug-drug interactions in patients;
  • the present disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating thrombocytopenia, and the compound of formula I or a pharmaceutically acceptable salt thereof and a BCRP substrate do not produce drug-drug interaction in a patient's body effect.
  • the drug-drug interaction that does not produce clinical significance described in the present disclosure is the drug-drug interaction that does not produce clinical significance.
  • the drug-drug interaction that does not produce clinical significance described in the present disclosure represents the systemic exposure
  • the clinical significance of the change is insufficient to take clinical measures, such as contraindication, caution, dosage or regimen adjustment, or other treatment monitoring.
  • a pointer substrate to determine whether an investigational drug is a pro-mutagenic drug, if the 90% confidence interval for the blood exposure ratio falls completely within the 80% to 125% equivalence range, then it is deemed not to be clinically significant drug-drug interactions (DDIs).
  • the present disclosure also provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, which is not as effective as taking the BCRP substrate alone. Dosing of BCRP substrates needs to be adjusted.
  • a patient described in the present disclosure is in need of administration of both a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a BCRP substrate.
  • the patients of the present disclosure are human patients.
  • the present disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of thrombocytopenia, and administering to a patient the compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, together with a single No dose adjustment of BCRP substrate is required compared to taking BCRP substrate.
  • the present disclosure also provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, the AUC of the BCRP substrate in plasma.
  • ⁇ is within the range of 80.00% to 125.00% of AUC 0- ⁇ when BCRP substrate is administered alone.
  • the present disclosure also provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, the AUC of the BCRP substrate in plasma.
  • t was within the range of 80.00% to 125.00% of AUC 0-t when BCRP substrate was administered alone.
  • the present disclosure also provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, the Cmax of the BCRP substrate in plasma is in the Within the range of 80.00% to 125.00% of Cmax when taking BCRP substrate alone.
  • the present disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating thrombocytopenia, and administering to a patient the compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, the BCRP substrate
  • the plasma Cmax of the BCRP substrate is in the range of 80.00% to 125.00% of the Cmax when the BCRP substrate is taken alone, and the AUC 0-t of the BCRP substrate in the plasma is 80.00 of the AUC 0-t of the BCRP substrate alone.
  • Within the range of % ⁇ 125.00% or the AUC 0- ⁇ of BCRP substrate in plasma was within the range of 80.00% ⁇ 125.00% of the AUC 0- ⁇ of taking BCRP substrate alone.
  • the present disclosure administers to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate, the AUC 0- ⁇ of the BCRP substrate in plasma , Cmax or AUCo -t were within the range of 80.00% to 125.00% of AUCo - ⁇ , Cmax or AUCo -t when BCRP substrate was administered alone.
  • a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate can be administered to a patient, and the mean AUC 0- ⁇ , C max or AUC 0-t of the BCRP substrate in plasma
  • the ratio to the mean of AUC0 - ⁇ , Cmax or AUC0 -t of BCRP substrate when BCRP substrate was administered alone fell within the range of 80.00% to 125.00%.
  • the mean may be an arithmetic mean, geometric mean, geometric least squares mean and other mean types routinely selected by those skilled in the art.
  • the ratio of the mean values falls within the range of 80.00% to 125.00%, specifically, the geometric least squares mean ratio and its 90% confidence interval fall within the range of 80.00% to 125.00%.
  • the BCRP substrates described in the present disclosure are compounds, active molecules, pharmaceutical compositions, drugs, and the like that have certain therapeutic activity.
  • the BCRP substrate may be a BCRP substrate known at the filing or priority date or validated after the filing or priority date.
  • the BCRP substrate is rosuvastatin or a pharmaceutically acceptable salt thereof, imatinib or a pharmaceutically acceptable salt thereof, irinotecan or a pharmaceutically acceptable salt thereof, lapatinib Nitrile or a pharmaceutically acceptable salt thereof, Methotrexate or a pharmaceutically acceptable salt thereof, Mitoxantrone or a pharmaceutically acceptable salt thereof, Sulfasalazine or a pharmaceutically acceptable salt thereof, or Topotecan or a pharmaceutically acceptable salt thereof
  • the BCRP substrate is rosuvastatin or a pharmaceutically acceptable salt thereof, and more preferably the BCRP substrate is rosuvastatin calcium.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.
  • the composition comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • rosuvastatin or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.
  • composition comprises a therapeutically effective amount of rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present disclosure also provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof and 10 mg of rosuvastatin or a pharmaceutically acceptable salt thereof, the rosuvastatin is in Cmax in plasma ranged from 80.00% to 125.00% of 11.8 ng/ml.
  • the present disclosure also provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof and 10 mg of rosuvastatin or a pharmaceutically acceptable salt thereof, the rosuvastatin is in AUC 0-t in plasma ranged from 80.00% to 125.00% of 120ng*h/ml.
  • the present disclosure also provides a method for treating thrombocytopenia, comprising administering to a patient a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof and 10 mg of rosuvastatin or a pharmaceutically acceptable salt thereof, the rosuvastatin is in AUC 0- ⁇ in plasma ranged from 80.00% to 125.00% of 123ng*h/ml.
  • the present disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating thrombocytopenia, and administering to a patient a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof and 10 mg of rosuvastatin or a pharmaceutically acceptable salt thereof, the Cmax of rosuvastatin in plasma is in the range of 80.00% to 125.00% of 11.8ng/ml, and the AUC 0-t of rosuvastatin in plasma is in the range of 120ng*h/ml Within the range of 80.00% to 125.00% or the AUC 0- ⁇ of rosuvastatin in plasma within the range of 80.00% to 125.00% of 123ng*h/ml.
  • the patient described in the present disclosure is in need of administration of both a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of rosuvastatin, wherein the
  • the patients also suffer from hypercholesterolemia or mixed dyslipidemia at the same time, wherein the patients with hypercholesterolemia or mixed dyslipidemia also include, according to clinical needs, it is necessary to administer rosuvastatin.
  • the present disclosure also provides a method for treating hypercholesterolemia or mixed dyslipidemia, comprising administering to a patient a therapeutically effective amount of rosuvastatin or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of the compound represented by formula I or its A pharmaceutically acceptable salt does not require dose adjustment of rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a method for treating hypercholesterolemia or mixed dyslipidemia, comprising administering to a patient 10 mg of rosuvastatin or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of the compound represented by formula I or its pharmaceutically acceptable With salt, the Cmax of rosuvastatin in plasma is in the range of 80.00% to 125.00% of 11.8ng/ml, and the AUC 0-t of rosuvastatin in plasma is in the range of 80.00% to 125.00 of 120ng*h/ml % range or the AUC 0- ⁇ of rosuvastatin in plasma was in the range of 80.00% to 125.00% of 123ng*h/ml.
  • the present disclosure also provides rosuvastatin or a pharmaceutically acceptable salt thereof for treating hypercholesterolemia or mixed dyslipidemia, and administering 10 mg of rosuvastatin or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of rosuvastatin to a patient
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof, the Cmax of rosuvastatin in plasma is in the range of 80.00% to 125.00% of 11.8ng/ml
  • the AUC 0-t of rosuvastatin in plasma is in the range of 80.00% to 125.00% of 11.8ng/ml.
  • Within the range of 80.00% to 125.00% of 120ng*h/ml or the AUC 0- ⁇ of rosuvastatin in plasma within the range of 80.00% to 125.00% of 123ng*h/ml.
  • the present disclosure also provides a method for administering formula I or a pharmaceutically acceptable salt thereof, comprising administering formula I or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof to a patient suffering from thrombocytopenia and mixed dyslipidemia at the same time With salt, no dose adjustment of rosuvastatin or a pharmaceutically acceptable salt is required.
  • the present disclosure also provides a method of administering formula I or a pharmaceutically acceptable salt thereof, comprising administering formula I or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof to a patient suffering from both thrombocytopenia and hypercholesterolemia salt, no dose adjustment of rosuvastatin or a pharmaceutically acceptable salt is required.
  • the 10 mg of rosuvastatin or a pharmaceutically acceptable salt thereof 10 mg is the weight of rosuvastatin in rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the BCRP substrate is rosuvastatin or a pharmaceutically acceptable salt thereof
  • the administered dose is 5-30 mg.
  • the administration dose is the weight of rosuvastatin in a single administration of rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the administration dose is preferably 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg.
  • the total daily dose administered is 5-30 mg.
  • the total daily dose is the total weight of rosuvastatin in the daily dose of rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the total daily dose administered is preferably 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg.
  • the administration frequency is once a day, twice a day or three times a day.
  • Formula I or a pharmaceutically acceptable salt thereof is administered in a dose of 1-30 mg.
  • the described dosage is the weight of the compound of formula I in a single dose of formula I or a pharmaceutically acceptable salt thereof.
  • the administration dose is preferably 1.0 mg, 2.0 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg.
  • the frequency of administration of Formula I or a pharmaceutically acceptable salt thereof is once daily, twice daily, or three times daily.
  • administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a BCRP substrate to a patient refers to administering formula I or a pharmaceutically acceptable salt thereof within a certain period of time and at least one BCRP substrate, the time period can be within one dosing cycle, optionally within 72 hours, within 36 hours, within 48 hours, within 24 hours, within 20 hours, within 18 hours, within 16 hours , within 12 hours, within 10 hours, within 8 hours, within 6 hours, within 4 hours, within 2 hours, within 1 hour, within 0.5 hours, or in combination.
  • taking BCRP substrate alone refers to taking BCRP substrate without concomitant administration with other compounds, active molecules, pharmaceutical compositions, drugs, etc. that produce drug-drug interactions.
  • the dosage indicated in the drug insert; in some embodiments, the dosage or therapeutically effective amount of the BCRP substrate taken alone can be understood as giving the patient according to clinical treatment needs without considering drug-drug interactions of the active ingredient in it.
  • Thrombocytopenia as used in this disclosure includes, but is not limited to, primary immune thrombocytopenia (ITP), bone marrow failure diseases such as aplastic anemia (AA), hematological malignancies such as myeloproliferation Myelodysplastic syndromes (MDS), chronic liver disease, and thrombocytopenia caused by chemotherapy, radiotherapy, bacterial or viral infections (HIV, HCV, etc.).
  • ITP primary immune thrombocytopenia
  • AA aplastic anemia
  • MDS myeloproliferation Myelodysplastic syndromes
  • chronic liver disease thrombocytopenia caused by chemotherapy, radiotherapy, bacterial or viral infections (HIV, HCV, etc.
  • the compounds of formula I described in the present disclosure exist in tautomers. Although the structural formula of formula I is drawn as some isomer forms for brevity, the present invention may include all isomers, such as tautomers. Isomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers. The tautomer of the compound shown in formula I also belongs to the protection scope of the present disclosure, such as:
  • the present disclosure provides a treatment method of formula I or a pharmaceutically acceptable salt thereof, when formula I or a pharmaceutically acceptable salt thereof and a BCRP substrate are taken at the same time, drug-drug interactions of clinical significance will not occur, and the drug-drug interaction with single Cmax , AUC 0-t , AUC 0- of rosuvastatin in plasma after combined medication (rosuvastatin calcium tablet + formula I or its pharmaceutically acceptable salt) compared with medication (rosuvastatin calcium tablet)
  • the geometric least squares mean ratio of ⁇ and its 90% confidence interval are 112.87% (101.95%-124.96%), 110.28% (103.93%-117.01%), and 110.28% (103.67%-117.32%), respectively.
  • Example 1 Pharmacokinetic effects of test drugs on BCRP substrate rosuvastatin.
  • Test drug diethanolamine salt tablet of the compound represented by formula I, produced and provided by Jiangsu Hengrui, specifications: 2.5mg/tablet and 5mg/tablet.
  • Rosuvastatin calcium tablets produced by AstraZeneca Pharmaceuticals (China) Co., Ltd., with a specification of 10mg/tablet.
  • Subjects were checked during the screening period before administration (D-14 ⁇ D-2), and the qualified subjects were admitted to the Phase I clinical trial ward in D-1. They had a light diet in the evening, and then fasted for 10 hours overnight. .
  • the next morning (D1), oral administration of 10 mg of rosuvastatin calcium tablets (1 tablet of 10 mg specification) with about 240 ml of warm water on an empty stomach, fasting within 4 hours after administration, and water fasting within 1 hour before and after administration.
  • test drug 1 tablet of 2.5 mg and 5 mg each
  • 7.5 mg of the test drug was administered on an empty stomach in the morning, and taken with about 240 mL of warm water.
  • fast for at least 2 hours before administration fast for 2 hours after administration, and fast for 1 hour before and after administration.
  • subjects After administration, subjects should avoid strenuous exercise and prolonged bed rest, refrain from taking fruit juice, tea, coffee, wine and other caffeine-containing and alcoholic beverages, and smoking.
  • Subjects should swallow the study drug whole and not chew the drug prior to swallowing. After taking the medicine, the staff needs to check the subject's mouth and hands to ensure the subject's compliance with the medication procedure.
  • Venous blood was collected from each subject within 1h before the administration of the test drug on the 9th, 10th and 11th days, and each blood collection was about 4mL, of which the blood sample 1h before the administration on the 11th day can be used for PK analysis of rosuvastatin. .
  • a mixed-effects model was used for statistical analysis of AUC 0 - t , AUC 0- ⁇ (if computable) and C max of rosuvastatin in concomitant and single-agent states after log-transformation.
  • the treatment group (concomitant drug, single drug) was used as a fixed effect, and the subject was a random effect. From the mean difference estimated by the model (combination drug-single drug) and its 90% confidence interval, take the antilog to obtain the geometric mean ratio of the corresponding PK parameter (combination drug/single drug) and its 90% confidence interval estimate, and evaluate the test drug.
  • GeoLSM is the geometric least squares mean
  • Ratio is the geometric least squares mean ratio

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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，本公开提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐，其中所述的患者中式I所示的化合物或其可药用盐与BCRP底物在患者体内不产生药物-药物相互作用。

Description

一种血小板生成素受体激动剂的给药方案
本申请要求申请日为2021年4月30日的中国专利申请CN202110481005.0的优先权。本申请引用上述中国专利申请的全文。
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。
艾曲泊帕(Eltrombopag，
Figure PCTCN2022090302-appb-000001
)是GSK公司开发的口服小分子TPORA。小分子TPORA作用于TPO-R的跨膜区域，激活人类TPO-R的信号传导通路，并导致骨髓干细胞中巨核细胞的增殖及分化。此外，小分子TPORA还可刺激造血干细胞，促进骨髓再生障碍的复苏用于治疗难治性再生障碍性贫血。目前批准的艾曲泊帕治疗适应症包括：(1)对糖皮质激素、免疫球蛋白或脾切除疗效欠佳的成人及儿童(1周岁以上)慢性原发免疫性血小板减少症(ITP)，该成人适应征于2008年11月获得美国FDA批准，并且在2009年在欧洲获准，儿童适应征于2018年8月被美国FDA批准；(2)慢性丙型肝炎合并血小板缺乏症(Chronic Hepatitis C-associated Thrombocytopenia)，该适应征于2012年2月获得美国FDA的批准，2013年也在欧洲获得了批准；(3)联合标准免疫抑制治疗作为一线治疗用于成人及儿童(2周岁以上)重型再生障碍性贫血患者，该适应征于2018年11月获得FDA批准；(4)免疫抑制治疗应答不佳的重度再生障碍性贫血患者，该适应征于2014年8月获得美国FDA批准。此外，艾曲泊帕于2018年在中国获批上市用于 成人及12岁以上儿童慢性ITP患者治疗。
2011年GSK公开了联合用药艾曲波帕和瑞舒伐他汀的临床试验数据Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers，显示艾曲波帕与瑞舒伐他汀联合用药使研究人群中瑞舒伐他汀的血浆几何平均AUC(90％置信区间)增加了55％(42％，69％)，C max增加了103％(82％，126％)，艾曲波帕的药品说明书中建议服用艾曲波帕时，若同时服用瑞舒伐他汀，建议将瑞舒伐他汀的剂量减少50％，并密切监测其相关副作用。
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，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。
Figure PCTCN2022090302-appb-000002
在已进行的临床试验中，治疗ITP有效率主要临床指标为治疗8周后应答者(定义为血小板计数≥50×109/L)的比例，给予ITP患者式I或其可药用盐，到达主要临床终点患者为58.9％(2.5mg组)或64.3％(5.0mg组)；根据NCT01762761公开的临床试验结果，艾曲波帕到达主要临床终点患者为57.7％(60/104 25mg)，式I或其可药用盐在治疗效果上，与艾曲波帕相当，达到主要临床终点的患者比例稍多。
根据体外研究证实，式I或其可药用盐是乳腺癌耐药蛋白(BCRP)的抑制剂和底物，BCRP是一种外排转运体，它可将药物从肝脏运输到胆汁中，同时也限制肠道药物吸收利用，他汀类药物如瑞舒伐他汀、阿托伐他汀、氟伐他汀和辛伐他汀均为BCRP底物。瑞舒伐他汀被称为是“超级他汀”，能够有效降低血脂、逆转动脉粥样斑块、降低动脉粥样硬化炎性指标，并且能在高风险和低风险患者中减少心血管事件发生率和死亡率，作为饮食控制和其它降脂措施(如LDL去除疗法)的辅助治疗，持续用药时间较长。相比于 其他他汀类药物，瑞舒伐他汀具有肝选择性高、亲油性低、不良反应低的优势，常见的不良反应是肌肉毒性，严重者可引起横纹肌溶解，这种不良反应或直接或间接与他汀类药合用的其他药物所产生的药动学相互作用有关。
BCRP对瑞舒伐他汀的药物处置很重要，在接受瑞舒伐他汀治疗的受试者中，BCRP(421CA)纯合子或BCRP(421AA)纯合子与BCRP(421CC)对照组相比，服用瑞舒伐他汀后的暴露量相差两倍。因此，服用式I或其可药用盐后可能会增加BCRP底物瑞舒伐他汀的暴露量。
本公开提供了一种式I或其可药用盐的治疗方法，当同时服用式I或其可药用盐和BCRP底物时，不会产生临床意义上的药物-药物相互作用，与单用药(瑞舒伐他汀钙片)相比，联合用药(瑞舒伐他汀钙片+式I或其可药用盐)后血浆中瑞舒伐他汀的C max、AUC 0-t、AUC 0-∞的几何最小二乘均值比值及其90％置信区间分别为112.87％(101.95％～124.96％)、110.28％(103.93％～117.01％)、110.28％(103.67％～117.32％)。血浆中瑞舒伐他汀的C max、AUC 0-t、AUC 0-∞的几何均值比值及其90％置信区间均落在80.00％～125.00％范围之内，即可认为式I或其可药用盐对瑞舒伐他汀的PK暴露量没有影响。乳腺癌耐药蛋白(BCRP)底物瑞舒伐他汀钙片联合BCRP抑制剂式I或其可药用盐给药后不会出现具有临床意义的药物-药物相互作用。即式I或其可药用盐与瑞舒伐他汀联合使用时，不需要调整瑞舒伐他汀的给药剂量。乳腺癌耐药蛋白(BCRP)底物瑞舒伐他汀钙片联合式I或其可药用盐给药后在健康受试者的安全性和耐受性良好。
发明内容
本公开提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物在患者体内不产生药物-药物相互作用；
Figure PCTCN2022090302-appb-000003
本公开还提供一种用于治疗血小板减少的式I所示的化合物或其可药用盐，式I所示的化合物或其可药用盐与BCRP底物在患者体内不产生药物-药物相互作用。
本公开所述的不产生药物-药物相互作用，即为不产生临床意义的药物-药物相互作用，具体来说，本公开所述的不产生临床意义的药物-药物相互作用，表示系统暴露量改变的临床意义不足以采取临床措施，如禁用、慎用、用药剂量或方案调整或者其他治疗监测。或使用指针底物来确定在研药物是否为促变药物时，如果血液暴露比的90％置信区间完全落在80％～125％的等效性范围之内，则认定不会出现临床显著性的药物-药物相互作用(DDI)。
本公开还提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，与单独服用BCRP底物相比，不需要调整BCRP底物的给药剂量。
在某些实施方案中，本公开所述的患者是既需要给予治疗有效量的式I所示的化合物或其可药用盐，同时还需要给予治疗有效量的BCRP底物。
在某些实施方案中，本公开所述的患者是人类患者。
本公开还提供一种用于治疗血小板减少的式I所示的化合物或其可药用盐，给予患者式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，与单独服用BCRP底物相比，不需要调整BCRP底物的给药剂量。
本公开还提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的AUC 0-∞在单独服用BCRP底物时AUC 0-∞的80.00％～125.00％范围之内。
本公开还提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的AUC 0-t在单独服用BCRP底物时AUC 0-t的80.00％～125.00％范围之内。
本公开还提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的C max在单独服用BCRP底物时C max的80.00％～125.00％范围之内。
本公开还提供一种用于治疗血小板减少的式I所示的化合物或其可药用盐，给予患 者式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的C max在单独服用BCRP底物时C max的80.00％～125.00％范围之内、BCRP底物在血浆中的AUC 0-t在单独服用BCRP底物时AUC 0-t的80.00％～125.00％范围之内或BCRP底物在血浆中的AUC 0-∞在单独服用BCRP底物AUC 0-∞的80.00％～125.00％范围之内。
在某些实施方案中，本公开所述的给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的AUC 0-∞、C max或AUC 0-t在单独服用BCRP底物时AUC 0-∞、C max或AUC 0-t的80.00％～125.00％范围之内。具体可以为给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的AUC 0-∞、C max或AUC 0-t均值与单独服用BCRP底物时BCRP底物的AUC 0-∞、C max或AUC 0-t的均值的比值落入80.00％～125.00％范围之内。其中所述的均值可以是算数均值、几何均值、几何最小二乘均值等本领域技术人员常规选择的均值类型。其中所述的均值的比值落入80.00％～125.00％范围之内，具体可以是几何最小二乘均值比值及其90％置信区间落入80.00％～125.00％范围之内。
在某些实施方案中，本公开中所述的BCRP底物为具有一定治疗活性的化合物、活性分子、药物组合物、药物等。BCRP底物可以是申请日或优先权日前已知的或是申请日或优先权日后经验证的BCRP底物。
在某些实施方案中，其中所述的BCRP底物为瑞舒伐他汀或其可药用盐、伊马替尼或其可药用盐、伊立替康或其可药用盐、拉帕替尼或其可药用盐、甲氨蝶呤或其可药用盐、米托蒽醌或其可药用盐、柳氮磺胺吡啶或其可药用盐或拓扑替康或其可药用盐，优选BCRP底物为瑞舒伐他汀或其可药用盐，更优选BCRP底物为瑞舒伐他汀钙。
在某些实施方案中，其中所述的式I所示的化合物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，其中所述的组合物包括治疗有效量的式I所示的化合物或其可药用盐和药学上可接受的载体。
在某些实施方案中，其中所述的瑞舒伐他汀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，其中所述的组合物包括治疗有效量的瑞舒伐他汀或其可药用盐 和药学上可接受的载体。
本公开还提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和10mg的瑞舒伐他汀或其可药用盐，瑞舒伐他汀在血浆中的C max在11.8ng/ml的80.00％～125.00％范围内。
本公开还提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和10mg的瑞舒伐他汀或其可药用盐，瑞舒伐他汀在血浆中的AUC 0-t在120ng*h/ml的80.00％～125.00％范围内。
本公开还提供一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和10mg的瑞舒伐他汀或其可药用盐，瑞舒伐他汀在血浆中的AUC 0-∞在123ng*h/ml的80.00％～125.00％范围内。
本公开还提供一种用于治疗血小板减少的式I所示的化合物或其可药用盐，给予患者治疗有效量的式I所示的化合物或其可药用盐和10mg的瑞舒伐他汀或其可药用盐，瑞舒伐他汀在血浆中的C max在11.8ng/ml的80.00％～125.00％范围内、瑞舒伐他汀在血浆中的AUC 0-t在120ng*h/ml的80.00％～125.00％范围内或瑞舒伐他汀在血浆中的AUC 0-∞在123ng*h/ml的80.00％～125.00％范围内。
在某些实施方案中，本公开所述的患者是既需要给予治疗有效量的式I所示的化合物或其可药用盐，同时还需要给予治疗有效量的瑞舒伐他汀，其中所述的患者还同时患有高胆固醇血症或混合型血脂异常症，其中所述患有高胆固醇血症或混合型血脂异常症的患者还包括，根据临床需要，有给予瑞舒伐他汀的必要。
本公开还提供一种治疗高胆固醇血症或混合型血脂异常症的方法，包括给予患者治疗有效量的瑞舒伐他汀或其可药用盐和治疗有效量的式I所示的化合物或其可药用盐，不需要调整瑞舒伐他汀或其可药用盐的给药剂量。
本公开还提供一种治疗高胆固醇血症或混合型血脂异常症的方法，包括给予患者10mg的瑞舒伐他汀或其可药用盐和治疗有效量的式I所示的化合物或其可药用盐，瑞舒伐他汀在血浆中的C max在11.8ng/ml的80.00％～125.00％范围内、瑞舒伐他汀在血浆中的AUC 0-t在120ng*h/ml的80.00％～125.00％范围内或瑞舒伐他汀在血浆中的AUC 0-∞在123ng*h/ml的80.00％～125.00％范围内。
本公开还提供一种用于治疗高胆固醇血症或混合型血脂异常症的瑞舒伐他汀或其可药用盐，给予患者10mg的瑞舒伐他汀或其可药用盐和治疗有效量的式I所示的化合物或其可药用盐，瑞舒伐他汀在血浆中的C max在11.8ng/ml的80.00％～125.00％范围内、瑞舒 伐他汀在血浆中的AUC 0-t在120ng*h/ml的80.00％～125.00％范围内或瑞舒伐他汀在血浆中的AUC 0-∞在123ng*h/ml的80.00％～125.00％范围内。
本公开还提供一种式I或其可药用盐的给药方法，包括给予同时患有血小板减少和混合型血脂异常症患者式I或其可药用盐和瑞舒伐他汀或其可药用盐，不需要调整瑞舒伐他汀或其可药用盐的给药剂量。
本公开还提供一种式I或其可药用盐的给药方法，包括给予同时患有血小板减少和高胆固醇血症患者式I或其可药用盐和瑞舒伐他汀或其可药用盐，不需要调整瑞舒伐他汀或其可药用盐的给药剂量。
在某些实施方案中，所述的10mg的瑞舒伐他汀或其可药用盐，10mg为瑞舒伐他汀或其可药用盐中瑞舒伐他汀的重量。
在某些实施方案中，其中所述的BCRP底物为瑞舒伐他汀或其可药用盐，给药剂量为5-30mg。其中所述的给药剂量为单次给药瑞舒伐他汀或其可药用盐中瑞舒伐他汀的重量。给药剂量优选5mg、10mg、15mg、20mg、25mg、30mg。
在某些实施方案中，其中所述的BCRP底物为或其可药用盐，每日给药剂量总量为5-30mg。其中所述的每日给药剂量总量为每日给药瑞舒伐他汀或其可药用盐中瑞舒伐他汀的总重量。每日给药剂量总量优选5mg、10mg、15mg、20mg、25mg、30mg。
在某些实施方案中，其中所述的BCRP底物为瑞舒伐他汀或其可药用盐，给药频次为每日一次、每日两次或每日三次。
在某些实施方案中，其中所述式I所示的化合物或其可药用盐为式I二乙醇胺盐。所述的式I二乙醇胺盐具体为下式结构：
Figure PCTCN2022090302-appb-000004
在某些实施方案中，其中式I或其可药用盐给药剂量为1-30mg。其中所述的给药剂 量为单次给药式I或其可药用盐中式I化合物的重量。给药剂量优选1.0mg、2.0mg、2.5mg、5mg、7.5mg、10mg、15mg、20mg、25mg、30mg。
在某些实施方案中，其中式I或其可药用盐给药频次为每日一次、每次两次或每日三次。
本公开中所述的“给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物”是指在一定时间期限内给予式I或其可药用盐和至少一种BCRP底物，所述的时间期限可以是一个给药周期内，可选72小时以内、36小时以内、48小时以内、24小时以内、20小时以内、18小时以内、16小时以内、12小时以内、10小时以内、8小时以内、6小时以内、4小时以内、2小时以内、1小时以内、0.5小时以内或一并服用。优选24小时以内、20小时以内、18小时以内、16小时以内、12小时以内、10小时以内、8小时以内、6小时以内、4小时以内、2小时以内、1小时以内、0.5小时以内或一并服用。
本公开中所述的“单独服用BCRP底物”是指服用BCRP底物时不与其他产生药物-药物相互作用的化合物、活性分子、药物组合物、药物等同时服用，通常为临床使用中依据药品说明书标注的给药剂量；在某些实施方案中，单独服用BCRP底物的给药剂量或治疗有效量可以理解为根据临床治疗需要，在不考虑药物-药物相互作用的前提下，给予患者的其中活性成分的重量。
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。
本公开中所述的式I所示的化合物存在互变异构体，虽然为简便起见将式I结构式画成某些异构体形式，但是本发明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。式I所示的化合物的互变异构体也属 于本公开保护范围之内，例如：
Figure PCTCN2022090302-appb-000005
本公开提供了一种式I或其可药用盐的治疗方法，当同时服用式I或其可药用盐和BCRP底物时，不会产生临床意义上的药物-药物相互作用，与单用药(瑞舒伐他汀钙片)相比，联合用药(瑞舒伐他汀钙片+式I或其可药用盐)后血浆中瑞舒伐他汀的C max、AUC 0-t、AUC 0-∞的几何最小二乘均值比值及其90％置信区间分别为112.87％(101.95％～124.96％)、110.28％(103.93％～117.01％)、110.28％(103.67％～117.32％)。血浆中瑞舒伐他汀的C max、AUC 0-t、AUC 0-∞的几何均值比值及其90％置信区间均落在80.00％～125.00％范围之内，即可认为式I或其可药用盐对瑞舒伐他汀的PK暴露量没有影响。乳腺癌耐药蛋白(BCRP)底物瑞舒伐他汀钙片联合BCRP抑制剂式I或其可药用盐给药后不会出现具有临床意义的药物-药物相互作用。即式I或其可药用盐与瑞舒伐他汀联合使用时，不需要调整瑞舒伐他汀的给药剂量。乳腺癌耐药蛋白(BCRP)底物瑞舒伐他汀钙片联合式I或其可药用盐给药后在健康受试者的安全性和耐受性良好。
具体实施方式
实施例1：试验药对BCRP底物瑞舒伐他汀的药代动力学影响。
1、试验药物
试验药：式I所示化合物的二乙醇胺盐片剂，由江苏恒瑞生产并提供，规格：2.5mg/片和5mg/片。
瑞舒伐他汀钙片，由阿斯利康药业(中国)有限公司生产，规格10mg/片。
2、入排标准
受试者必须符合以下所有条件才能入组本研究：
1.自愿在与本试验相关的活动开始前签署知情同意书，并能够理解本试验的程序和方法，愿意严格遵守临床试验方案完成本试验；
2.年龄在18～55岁(含临界值)，男女不限；
3.男性体重≥50.0kg，女性体重≥45.0kg，且体重指数(BMI)在19～26kg/m2(包括两端值)；
4.健康状况良好：无心、肝、肾、消化道、神经系统等病史；体格检查及各项实验室检查结果正常或异常无临床意义，ECG正常或异常无临床意义；
5.签署知情同意书至末次给药后3个月内无生育计划，并且同意采取有效的避孕措施者；
6.能够和研究者进行良好的沟通，并且理解和遵守本项研究的各项要求。
受试者若符合以下任何一项将不得进入本研究：
1.既往或目前正患有循环系统、内分泌系统、神经系统、消化系统、呼吸系统、血液学、免疫学、精神病学及代谢异常等任何临床严重疾病者或能干扰试验结果的任何其他疾病；
2.有深静脉血栓病史或其他血栓性疾病者；
3.具有HMG-CoA还原酶抑制剂或贝特类药物的肌肉毒性史；
4.筛查时12-ECG检查男性QTc＞450ms或女性QTc＞460ms并且经研究者判断有临床意义者；
5.乙肝表面抗原、丙型肝炎抗体、梅毒抗体、HIV抗体检查阳性者；
6.妊娠检查阳性者；
7.过敏体质，或对式I所示化合物或其可药用盐的片和瑞舒伐他汀钙片中的任何成 份。
3、给药方案
受试者于给药前(D-14～D-2)进行筛选期检查，筛选合格的受试者于D-1入住I期临床试验病房，晚上统一清淡饮食，之后禁食不禁水10h过夜。次日早上(D1)用约240ml温水空腹口服瑞舒伐他汀钙片10mg(10mg规格1片)，给药后4h内禁食，给药前后1h内禁水。
第6～10天(D6～D10)早上空腹给予试验药7.5mg(2.5mg和5mg规格各1片)，用约240mL温水送服。多次给药期间，给药前至少空腹2h，给药后2h内禁食，给药前后1h内禁水。
第11天(D11)早上同时空腹给予瑞舒伐他汀钙片10mg和试验药7.5mg(先服用瑞舒伐他汀钙片10mg并开始计时，再服用试验药7.5mg)，用约240mL温水送服。给药前禁食至少10h，给药前后1h内禁水，给药后4h内禁食。
给药后受试者避免剧烈运动及长时间卧床，禁服果汁和茶、咖啡、酒等含咖啡因和醇类饮料，并禁止吸烟。
受试者应将研究药物完整吞入，在吞入之前不能咀嚼药物。服药后工作人员需要检查受试者的口腔及双手，以确保受试者对服药程序的依从性。
4、药代动力学评价
用于瑞舒伐他汀PK分析的血样检测
每位受试者在第一天瑞舒伐他汀钙片给药前1h内，给药后0.5h(±1.5min)、1h(±3min)、1.5h(±3min)、2h(±5min)、3h(±5min)、4h(±10min)、5h(±10min)、6h(±10min)、8h(±10min)、12h(±10min)、24h(±1h)、36h(±1h)、48h(±1h)和72h(±1h)，在第11天联合用药给药前1h内，给药后0.5h(±1.5min)、1h(± 3min)、1.5h(±3min)、2h(±5min)、3h(±5min)、4h(±10min)、5h(±10min)、6h(±10min)、8h(±10min)、12h(±10min)、24h(±1h)、36h(±1h)、48h(±1h)和72h(±1h)共30个时间点采集静脉血，每次采血约4mL。
用于试验药PK分析的血样检测
每位受试者在第9、10和11天试验药给药前1h内采集静脉血，每次采血约4mL，其中第11天给药前1h血样可与用于瑞舒伐他汀PK分析血样。
5、药物-药物相互作用分析
采用混合效应模型对经对数转换后合并用药及单药使用状态下瑞舒伐他汀的AUC 0- t、AUC 0-∞(如可计算)和C max进行统计分析。将治疗组别(合并用药、单药)作为固定效应，受试者为随机效应。由模型估计的均数差(合并用药-单药)及其90％置信区间取反对数得到相应PK参数几何均数比值(合并用药/单药)及其90％置信区间估计值，评价试验药对瑞舒伐他汀的PK影响。
6、试验结果
共计入组受试者14例
表1式I二乙醇胺盐片对瑞舒伐他汀的PK影响分析结果
Figure PCTCN2022090302-appb-000006
Figure PCTCN2022090302-appb-000007
注释：GeoLSM为几何最小二乘均值；Ratio为几何最小二乘均值比值。

Claims (21)

  1. 一种治疗血小板减少的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，与单独服用BCRP底物相比，不需要调整BCRP底物的给药剂量；
    Figure PCTCN2022090302-appb-100001
  2. 根据权利要求1所述方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的AUC 0-∞在单独服用BCRP底物时AUC 0-∞的80.00％～125.00％范围之内。
  3. 根据权利要求1所述方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的C max在单独服用BCRP底物时C max的80.00％～125.00％范围之内。
  4. 根据权利要求1所述方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的BCRP底物，BCRP底物在血浆中的AUC 0-t在单独服用BCRP底物时AUC 0-t的80.00％～125.00％范围之内。
  5. 根据权利要求1-4中任一项所述的方法，其中所述的BCRP底物为瑞舒伐他汀或其可药用盐、伊马替尼或其可药用盐、伊立替康或其可药用盐、拉帕替尼或其可药用盐、甲氨蝶呤或其可药用盐、米托蒽醌或其可药用盐、柳氮磺胺吡啶或其可药用盐或拓扑替康或其可药用盐，优选BCRP底物为瑞舒伐他汀或其可药用盐，更优选BCRP底物为瑞舒伐 他汀钙。
  6. 根据权利要求1-5中任一项所述的方法，其中所述的患者为人类患者。
  7. 根据权利要求1-5中任一项所述的方法，其中所述的患者还需给予BCRP底物。
  8. 根据权利要求1-5中任一项所述的方法，其中所述的患者还患有高脂血症；优选所述的患者还患有高胆固醇血症或混合型血脂异常症。
  9. 一种治疗高胆固醇血症或混合型血脂异常症的方法，包括给予患者治疗有效量的瑞舒伐他汀或其可药用盐和治疗有效量的式I所示的化合物或其可药用盐，不需要调整瑞舒伐他汀或其可药用盐的给药剂量。
  10. 根据权利要求1-9中任一项所述的方法，其中所述的式I所示的化合物或其可药用盐以药物组合物的形式给药。
  11. 根据权利要求10所述的方法，其中所述的组合物包括治疗有效量的式I所示的化合物或其可药用盐和药学上可接受的载体。
  12. 根据权利要求1-9中任一项所述的方法，其中所述的瑞舒伐他汀或其可药用盐以药物组合物的形式给药。
  13. 根据权利要求12所述的方法，其中所述的组合物包括治疗有效量的瑞舒伐他汀或其可药用盐和药学上可接受的载体。
  14. 根据权利要求5-13中任一项所述的方法，其中所述的瑞舒伐他汀钙或其可药用盐，给药剂量为5-30mg，优选5mg、10mg、15mg或20mg；更优选10mg。
  15. 根据权利要求5-14中任一项所述的方法，其中所述的瑞舒伐他汀钙或其可药用盐，每日给药剂量总量为5-30mg，优选5mg、10mg、15mg、20mg或30mg。
  16. 根据权利要求5-14中任一项所述的方法，其中所述的瑞舒伐他汀钙或其可药用盐，给药频次为每日一次、每日两次或每日三次。
  17. 根据权利要求5-14中任一项所述的方法，其中所述的瑞舒伐他汀钙或其可药用盐与式I所示的化合物或其可药用盐的给药间隔时间在24小时以内。
  18. 根据权利要求1-17中任一项所述的方法，其中所述式I所示的化合物或其可药用盐为式I二乙醇胺盐。
  19. 根据权利要求1-18中任一项所述的方法，其中式I或其可药用盐给药剂量为1-30mg，优选2.5mg、5mg、7.5mg或15mg。
  20. 根据权利要求1-19中任一项所述的方法，其中式I或其可药用盐给药频次为每日一次、每次两次或每日三次。
  21. 根据权利要求1-20中任一项所述的方法，其中所述的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、慢性肝病或化疗引起患者血小板减少。
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WO2020143593A1 (zh) * 2019-01-08 2020-07-16 江苏恒瑞医药股份有限公司 双环取代吡唑酮偶氮类衍生物的给药方案

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