英文药名:VEMLIDY Tablets(Tenofovir Alafenamide Fumarate)
中文药名:替诺福韦艾拉酚胺(TAF)片
生产厂家:Gilead Sciences Inc.
ベムリディ錠25mg
药物分类名称 抗病毒化疗药物 批准日期:2017年2月 商標名 VEMLIDY Tablets 25mg 一般名 テノホビル アラフェナミドフマル酸塩 Tenofovir Alafenamide Fumarate(JAN) 化学名 1-Methylethyl N-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phenoxyphosphinoyl]-L-alaninate hemifumarate 分子式 (C21H29N6O5P)2・C4H4O4 分子量 1069.00 構造式
性状 白色至灰白色或白色至暗淡的黄色红色粉末 可溶性 易溶于甲醇,微溶于乙醇(99.5),微溶于水或2-丙醇,溶于乙腈或丙酮较少,极不溶于甲苯。 熔点 约132°C 分布系数 对数P = 1.6(1-辛醇/ pH7磷酸盐缓冲液) 批准条件 制定药品风险管理计划,适当实施。 药效药理 1. 作用机序 替诺福韦Arafenamido是具有在磷酰胺修饰的替诺福韦的(2'-脱氧腺苷单磷酸类似物)的前药。替诺福韦Arafenamido通过被动转运和肝摄取转运OATP1B1和OATP1B3并入原代肝细胞。替诺福韦Arafenamido,主要是由于在羧酸酯酶原代肝细胞1离岗主要由组织蛋白酶A水解是在HIV靶细胞中的PBMC或其他。细胞中的替诺福韦被磷酸化成为替诺福韦二磷酸盐,其是活性代谢物。替诺福韦二磷酸盐被HBV的逆转录酶吸收到病毒DNA链中以抑制HBV复制并阻止病毒DNA链伸长。 替诺福韦特异性地对HBV和HIV(HIV-1和HIV-2)起作用。针对包含线粒体DNA聚合酶γ磷酸盐哺乳动物DNA聚合酶替诺福韦2抑制作用很弱,多个体外试验的结果,包括线粒体DNA分析中,观察到线粒体没有毒性。 2. 抗病毒活性 使用HepG2细胞评估替诺福韦arafenamide对基因型A至H的HBV临床分离株的抗病毒活性。 替诺福韦arafenamide对分离株的50%有效浓度(EC50值)为34.7〜134.4 nmol/L,所有菌株的平均EC50值分别为86.6 nmol/L。 HepG2细胞的50%细胞毒浓度(CC50值)高于4400nmol/L。 在体外相互作用试验中,替诺福韦与核酸逆转录酶抑制剂,阿德福韦,恩曲他滨,恩替卡韦,拉米夫定,替比夫定(国内未经批准)联合显示无拮抗作用。 3. 耐药性 在对108例试验和110项试验中接受该药物的未经治疗和以前治疗的患者的联合分析中,病毒学突破(一旦HBV DNA的量变得小于69 IU/mL,然后两次 或HBV DNA量从Nadia值增加1.0log 10或更多)或24周后早期停止的患者以及在停药时HBV DNA的量为69IU/mL以上 使用基线和给药后的HBV分离株分析HBV DNA的核苷酸序列。 24例患者中有20例确定HBV DNA的核苷酸序列,其中2例为日本患者。 从这些分离物中,没有检测到与该药物的抗性相关的氨基酸的取代。 4. 交差耐性 包括已知对核苷逆转录酶抑制剂,进行了一系列的临床分离株的使用HepG2细胞进行评价替诺福韦Arafenamido的抗病毒活性的抗性突变。拉米夫定抗性突变(rtV173L+rtL180M+rtM204V,rtL180M+rtM204V和rtM204I)病毒显示出对替诺福韦Arafenamido灵敏度(相对平均倍数变化野生型EC50值在抗性突变体:小于2倍)。 恩替卡韦抗性突变(rtL180M+rtM204V+rtT184G,rtL180M+rtM204V+rtS202G和rtL180M+rtM204V+ rtM250V)病毒显示出对替诺福韦Arafenamido灵敏度。阿德福韦酯抗性突变RtA181T,在代rtA181V或rtN236T的一个残基,表明替诺福韦Arafenamido灵敏度,在rtA181V + rtN236T突变病毒,下降,观察到替诺福韦Arafenamido灵敏度(EC50值平均倍数变化:3.7次)。这些突变的临床意义是未知的。 适用症 VEMLIDY是一种乙型肝炎病毒(HBV)核苷类似物逆转录酶抑制剂和是适用为在有代偿的肝病成年中慢性乙型肝炎病毒感染的治疗。 剂量和剂量 成年人,每次服用25mg,每天一次。 包装规格 25mg:14錠/瓶
制造厂商 吉利德科学公司 完整说明书附件:http://www.info.pmda.go.jp/go/pack/6250045F1023_1_03/ Hepatitis B new drug TAF approved in Japan On December 19, Gillard announced that the Japanese Ministry of Health, Labor and Welfare approved Vemlidy (tenofovir aramide, TAF) 25mg once a day to inhibit hepatitis B virus replication. TAF is another prodrug of the other commonly used hepatitis B drug Viread (tenofovir dipivoxil, TDF) because TAF has a high blood stability and can be delivered to hepatocytes efficiently, so TAF is lower than Viread One-tenth (25mg / 300mg) can play a similar effect with the latter, but also to avoid the concentration of tenofovir in the blood is too high and improve the safety. TAF was approved in Japan based primarily on two 48-week, III, non-inferior studies (Study 108 and Study 110). Study 108 study included 425 patients with HBeAg negative (HBeAg) -positive patients who were randomized to Vemlidy or Viread for 2 weeks in a 2: 1 group for 48 weeks, 27 of whom were enrolled in 11 centers in Japan. Study 110 study included 873 HBeAg-positive patients who were randomized to Vemlidy or Viread at 2: 1 for 48 weeks. Forty-six patients were from 16 centers in Japan. The primary endpoint from the study was the percentage of patients with HBV DNA levels below 29 IU/mL at 48 weeks. The results showed that the percentage of patients with HBV DNA levels below 29 IU/mL in the TA study group was 94% (268/285) and 92.9% (130/140) in the TDF group, reaching a non-inferior endpoint. In the study 110 study, the proportion of patients with HBV DNA levels below 29 IU / mL in the TAF treatment group was 63.9% (371/581) and 66.8% (195/292) in the TDF group, reaching a non-inferior endpoint. "There are more than 1 million cases of hepatitis B in Japan, and we believe that Vemlidy can provide a new treatment option for this group of patients," said Norbert Bischofberger, Chief Scientific Officer and Executive Vice President, Gilead. On November 10, the FDA approved Vemlidy (tenofovir aramide, TAF) 25 mg once daily for the treatment of patients with chronic hepatitis B virus (HBV) infection with compensatory liver disease. November 11, the European Commission for the Use of Medicines (CHMP) made a positive recommendation for Vemlidy's listing application. It is also recommended to approve TAF 25mg once daily for adults or adolescents (aged ≥ 12 years, Weight ≥ 35 kg) chronic hepatitis B infection, which means that the EU will soon be formally approved Vemlidy.
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