Edoxaban is not extensively metabolized by CYP3A4 resulting in minimal drug-drug interactions. However, it does interact with drugs that inhibit p-gp (p-glycoprotein), which is used to transport edoxaban across the intestinal wall. Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4. The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.
来源:DrugBank
代谢
在第一阶段，所有受试者接受了单次口服60毫克艾多沙班的治疗，第二阶段在第7天同时给予600毫克利福平（2 x 300毫克胶囊，每日一次）和单次口服60毫克艾多沙班的联合治疗。两个治疗之间有一个6天的清洗期。测量了艾多沙班及其代谢物M4和M6的血浆浓度，并对凝血的药效学标志物进行了有限的评估。共有34名健康受试者参加；32名完成了研究。利福平与艾多沙班的联合使用减少了艾多沙班的暴露，但增加了活性代谢物的暴露。利福平使艾多沙班的表观口服清除率增加了33%，半衰期减少了50%。基于凝血酶原时间（PT）和活化部分凝血活酶时间（aPTT）的 抗凝效果，在早期时间点，与利福平联合使用时比单独使用艾多沙班的效果更好，这可能是由于活性代谢物的贡献增加。艾多沙班在这健康成人人群中耐受性良好。利福平减少了艾多沙班的暴露，同时增加了其活性代谢物M4和M6的暴露。早期时间点的PT和aPTT没有明显变化；然而，数据应谨慎解读。
... All subjects received a single oral 60 mg edoxaban dose in period 1, and 7 days of 600 mg rifampin (2 x 300 mg capsules once daily) with a single oral edoxaban 60 mg dose administered concomitantly on day 7 in period 2. A 6-day washout period separated the treatments. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of pharmacodynamic markers of coagulation were performed. In total, 34 healthy subjects were enrolled; 32 completed the study. Coadministration of rifampin with edoxaban decreased edoxaban exposure but increased active metabolite exposure. Rifampin increased apparent oral clearance of edoxaban by 33% and decreased its half-life by 50%. Anticoagulant effects based on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) with and without rifampin at early time points were maintained to a greater-than-expected degree than with edoxaban exposure alone, presumably because of an increased contribution from the active metabolites. Edoxaban was well tolerated in this healthy adult population. Rifampin reduced exposure to edoxaban while increasing exposure to its active metabolites M4 and M6. PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.
Edoxaban and its low-abundance, active metabolite M4 are substrates of P-glycoprotein (P-gp; MDR1) and organic anion transporter protein 1B1 (OATP1B1), respectively, and pharmacological inhibitors of P-gp and OATP1B1 can affect edoxaban and M4 pharmacokinetics (PK). In this integrated pharmacogenomic analysis, genotype and concentration-time data from 458 healthy volunteers in 14 completed phase 1 studies were pooled to examine the impact on edoxaban PK parameters of allelic variants of ABCB1 (rs1045642: C3435T) and SLCO1B1 (rs4149056: T521C), which encode for P-gp and OATP1B1. Although some pharmacologic inhibitors of P-gp and OATP1B1 increase edoxaban exposure, neither the ABCB1 C3435T nor the SLCO1B1 T521C polymorphism affected edoxaban PK. A slight elevation in M4 exposure was observed among SLCO1B1 C-allele carriers; however, this elevation is unlikely to be clinically significant as plasma M4 concentrations comprise <10% of total edoxaban levels.
The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.
Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4.
IDENTIFICATION AND USE: Edoxaban is a white to pale yellowish-white crystalline powder. It is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism following 5 to 10 days of initial therapy with a parenteral anticoagulant. HUMAN STUDIES: Overdose of the drug increases the risk of bleeding. Edoxaban increases the risk of hemorrhage and can cause serious, potentially fatal, bleeding. Patients should be promptly evaluated if any manifestations of blood loss occur during therapy. The drug should be discontinued if active pathological bleeding occurs. However, minor or "nuisance" bleeding is a common occurrence in patients receiving any anticoagulant and should not readily lead to treatment discontinuance. Edoxaban and its human-specific metabolite, M-4 were not genotoxic in in vitro human lymphocytes micronucleus test. ANIMAL STUDIES: Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day. In a rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day. Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was seen when edoxaban was administered orally at doses up to 300 mg/kg/day. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose in rats. In rabbits, no malformation was seen at doses up to 600 mg/kg/day. Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day. Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro chromosomal aberration tests but were not genotoxic in the in vitro bacterial reverse mutation (Ames test), in in vivo rat bone marrow micronucleus test, in in vivo rat liver micronucleus test, and in in vivo unscheduled DNA synthesis tests.
Edoxaban is associated with serum aminotransferase elevations greater than 3 times the upper limit of normal in 2% to 5% of treated patients. This rate is similar or lower than rates with warfarin or comparator arms. The elevations are generally transient and not associated with symptoms or jaundice. In premarketing studies, no instances of clinically apparent liver injury were reported, but there was little experience in large numbers of patients treated for extend periods of time. In large health care databases, the rate of liver injury has been somewhat less with edoxaban than rivaroxaban and apixaban, but the numbers of patients treated with edoxaban has been limited and the nature of the liver injury not described.
◉ Summary of Use during Lactation:Because no information is available on the use of edoxaban during breastfeeding and the drug is orally absorbable, an alternate drug is preferred while nursing a newborn or preterm infant.[1][2][3]
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Edoxaban, an oral direct factor Xa inhibitor, is in development for thromboprophylaxis, including prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). P-glycoprotein (P-gp), an efflux transporter, modulates absorption and excretion of xenobiotics. Edoxaban is a P-gp substrate, and several cardiovascular (CV) drugs have the potential to inhibit P-gp and increase drug exposure. /The objective of the study was/ to assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates/inhibitors. Drug-drug interaction studies with edoxaban and CV drugs with known P-gp substrate/inhibitor potential were conducted in healthy subjects. In 4 crossover, 2-period, 2-treatment studies, subjects received edoxaban 60 mg alone and coadministered with quinidine 300 mg (n = 42), verapamil 240 mg (n = 34), atorvastatin 80 mg (n = 32), or dronedarone 400 mg (n = 34). Additionally, edoxaban 60 mg alone and coadministered with amiodarone 400 mg (n = 30) or digoxin 0.25 mg (n = 48) was evaluated in a single-sequence study and 2-cohort study, respectively. Edoxaban exposure measured as area under the curve increased for concomitant administration of edoxaban with quinidine (76.7%), verapamil (52.7%), amiodarone (39.8%), and dronedarone (84.5%), and exposure measured as 24 hr concentrations for quinidine (11.8%), verapamil (29.1%), and dronedarone (157.6%) also increased. Administration of edoxaban with amiodarone decreased the 24-hr concentration for edoxaban by 25.7%. Concomitant administration with digoxin or atorvastatin had minimal effects on edoxaban exposure. Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
口服直接因子Xa抑制剂埃多沙班是一种P-糖蛋白（P-gp）底物，通过羧酸酯酶-1和细胞色素P450（CYP）3A4/5代谢。本研究调查了利福平诱导的P-gp和CYP3A4/5对埃多沙班通过CYP3A4/5途径的转运和代谢的影响。这是一项针对健康成人的单剂量埃多沙班研究的第1阶段、开放标签、两种治疗、两个周期、单序列药物相互作用研究。所有受试者在第1周期接受了单次口服60 mg埃多沙班剂量，在第2周期的第7天同时给予了7天的600 mg利福平（每天2 x 300 mg胶囊）和单次口服埃多沙班60 mg剂量。两次治疗之间有6天的清洗期。测量了埃多沙班及其代谢物M4和M6的血浆浓度，并对凝血的药效学标志物进行了有限评估。总共招募了34名健康受试者；32名完成了研究。利福平与埃多沙班联合使用降低了埃多沙班的暴露量，但增加了活性代谢物的暴露量。利福平使埃多沙班的表观口服清除率增加了33%，使其半衰期减少了50%。基于凝血酶原时间（PT）和活化部分凝血活酶时间（aPTT）的 抗凝作用在没有利福平和有 利福平的情况下都得到了维持，并且比单独埃多沙班暴露的程度更大，这可能是由于活性代谢物的贡献增加。埃多沙班在这健康成人人群中耐受性良好。利福平降低了埃多沙班的暴露量，同时增加了其活性代谢物M4和M6的暴露量。早期时间点的PT和aPTT没有明显变化；然而，这些数据应谨慎解读。
The oral direct factor Xa inhibitor edoxaban is a P-glycoprotein (P-gp) substrate metabolized via carboxylesterase-1 and cytochrome P450 (CYP) 3A4/5. The effect of rifampin-induced induction of P-gp and CYP3A4/5 on transport and metabolism of edoxaban through the CYP3A4/5 pathway was investigated in a single-dose edoxaban study. This was a phase 1, open-label, two-treatment, two-period, single-sequence drug interaction study in healthy adults. All subjects received a single oral 60 mg edoxaban dose in period 1, and 7 days of 600 mg rifampin (2 x 300 mg capsules once daily) with a single oral edoxaban 60 mg dose administered concomitantly on day 7 in period 2. A 6-day washout period separated the treatments. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of pharmacodynamic markers of coagulation were performed. In total, 34 healthy subjects were enrolled; 32 completed the study. Coadministration of rifampin with edoxaban decreased edoxaban exposure but increased active metabolite exposure. Rifampin increased apparent oral clearance of edoxaban by 33% and decreased its half-life by 50%. Anticoagulant effects based on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) with and without rifampin at early time points were maintained to a greater-than-expected degree than with edoxaban exposure alone, presumably because of an increased contribution from the active metabolites. Edoxaban was well tolerated in this healthy adult population. Rifampin reduced exposure to edoxaban while increasing exposure to its active metabolites M4 and M6. PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.
Edoxaban is eliminated primarily as unchanged drug in urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance.
来源:DrugBank
吸收、分配和排泄
分布容积
稳态分布容积为107升。
The steady state volume of distribution is 107 L.
来源:DrugBank
吸收、分配和排泄
清除
22 升/小时
22 L/hr
来源:DrugBank
吸收、分配和排泄
/MILK/ 没有人乳中埃多沙班存在的数据...埃多沙班在大鼠乳中存在。...
/MILK/ There are no data on the presence of edoxaban in human milk ... . Edoxaban was present in rat milk. ...
A compound represented by the general formula (1):
Q
1
-Q
2
-T
0
-N(R
1
)-Q
3
-N(R
2
)-T
1
-Q
4
(1)
wherein R
1
and R
2
are hydrogen atoms or the like; Q
1
is a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, or the like; Q
2
is a single bond or the like; Q
3
is a group
in which Q
5
is an alkylene group having 1 to 8 carbon atoms, or the like; and T
0
and T
1
are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof.
The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
申请人：Pharmacostech Co., Ltd. 주식회사 파마코스텍(120050086512) Corp. No ▼ 154511-0018683BRN ▼124-85-50991
公开号：KR20200106737A
公开（公告）日：2020-09-15
본 발명은 에독사반 벤젠술폰산염 1수화물 결정형 및 그 제조방법을 제공한다. 본 발명에 따른 신규 결정형인 벤젠술폰산염 1수화물의 제조가 용이하며 순도, 수율이 높으며, 안정성 및 흡습성 등이 우수한 특성을 가진다.
This is the Chinese translation of the text you provided:
本发明提供了对苯二甲酸盐1水合物的晶体形态及其制备方法。根据本发明，对苯二甲酸盐1水合物的新晶型制备容易，纯度高，收率高，稳定性和吸湿性等特性优越。
신규한 에독사반 염 화합물 및 이의 제조 방법
申请人：KYONGBO PHARM.CO.,LTD. 주식회사 경보제약(120030265371) Corp. No ▼ 164811-0001961BRN ▼312-81-04567
公开号：KR20200033698A
公开（公告）日：2020-03-30
본 발명의 다양한 실시예는 신규한 에독사반 염 화합물 및 이의 제조 방법에 관한 것이다. 본 발명의 다양한 실시예에 따르면, 신규한 에독사반 염은 종래의 에독사반 토실산염과 유사한 특성을 가지거나 더 우수한 특성을 나타내므로, 에독사반 토실산염을 대체하여 사용될 수 있다. 구체적으로, 신규한 에독사반 염의 수율, 순도, 안정성 및 흡습성에 따른 순도는 종래의 에독사반 토실산염보다 현저히 향상된 특성을 나타냈다. 또한, 용해도에 있어서 신규한 에독사반 염은 종래의 에독사반 토실산염과 동일 또는 유사한 특성을 보여 추후 제제화를 위한 별도의 연구 및 노력 없이도 용이하게 제제화할 수 있다. 또한, 흡습성에 있어서도 에독사반 토실산염과 동일 또는 유사한 특성을 가지므로 종래의 에독사반 토실산염을 대체할 수 있음을 확인하였다.
Processes for the Preparation of Edoxaban and Intermediates Thereof
申请人：Apotex Inc.
公开号：US20180179226A1
公开（公告）日：2018-06-28
The present invention provides processes for the preparation of Edoxaban (1) and salts thereof, as well as intermediates thereof. In particular, intermediate compounds and/or salts of the Formulae (3), (4), (6-A), (7-A), (8-A), (9-A) and (10-AS) are provided.
