近日，由葛兰素史克公司，辉瑞公司和Shionogi公司开发的整合酶抑制剂dolutegravir（商品名 TIVICAY）获FDA批准为每日一次的口服药物，HIV整合酶抑制剂，旨在与其他抗逆转录病毒制剂联合用于既往已治疗过、或初治HIV-1成人和12岁及以上体重至少40千克儿童感染者。 美国FDA药物评价和研究中心抗微生物产品室主任Edward Cox，M.D.，M.P.H. 说：“HIV-感染个体需要治疗方案个体化以配合其情况和他们的需求，”“对FDA批准新药像Tivicay增加已存在选择方案仍是优先政策。” 批准日期： 2013年8月 12日；公司：ViiV Healthcare TIVICAY（度鲁特韦[dolutegravir]）片剂，供口服使用 最初的美国批准：2013 最近的主要变化 适应症和用法：11/2017 剂量和管理：11/2017 警告和注意事项，肝毒性：11/2017 警告和注意事项，脂肪再分配（上一个）已删除：11/2017 警告和注意事项，不良反应的风险或病毒学应答的丧失：11/2017 作用机制 Dolutegravir是一种HIV-1抗逆转录病毒剂[见微生物学]。 适应症和用法 TIVICAY是一种人类免疫缺陷病毒1型（HIV-1）整合酶链转移抑制剂（INSTI），与下列药物联合使用： •其他抗逆转录病毒药物，用于治疗成人和体重至少30公斤的儿童患者中的HIV-1感染。 •rilpivirine作为治疗成人HIV-1感染的完全方案，用稳定的抗逆转录病毒疗法治疗至少6个月的病毒学受抑制者（HIV-1 RNA低于50拷贝/ mL）替代目前的抗逆转录病毒治疗方案没有治疗失败的历史或与抗逆转录病毒剂抗性相关的已知替代。 剂量和给药 可能不考虑食物。 成人人口 推荐剂量 治疗初治或经历过INSTI初治或病毒学抑制（HIV-1 RNA <50拷贝/ mL）的成年人改用dolutegravir加rilpivirinea。 每日一次50mg 与某些UGT1A或CYP3A诱导剂联合给药时，未经治疗或接受过治疗的INSTI-naïve。 50毫克，每天两次 INSTI经历了与某些INSTI相关的耐药替代或临床疑似INSTI抵抗b。 50毫克，每天两次 对于那些转用dolutegravir加rilpivirine的患者，Rilpivirine剂量为25 mg。 b如果可能，应考虑不包括代谢诱导剂的替代组合。 儿科患者：（未接受治疗或接受治疗的INSTI天真患者，体重至少30公斤）。 •如果至少40公斤：推荐剂量是TIVICAY 50毫克，每天一次。 •30公斤至小于40公斤的患者：推荐剂量为TIVICAY 35毫克，每天一次。 •如果某些UGT1A或CYP3A诱导剂是共同给药的，那么将TIVICAY的基于体重的剂量调整为每日两次。 剂型和强度 片剂：10mg，25mg和50mg 禁忌症 •以前对dolutegravir的过敏反应。 •与多非利特合用。 警告和注意事项 •已报告以皮疹，体质结构和器官功能障碍（包括肝损伤）为特征的超敏反应。如果出现过敏反应的体征或症状，立即停止TIVICAY和其他可疑药物，因为停止治疗的延迟可能会导致危及生命的反应。 包装提供/储存和处理 TIVICAY片剂10毫克是白色圆形薄膜包装双凸面片剂，一边是“SV 572”，另一边是“10”。 一瓶30片装有儿童安全封口并装有干燥剂的瓶子。 NDC 49702-226-13。 在原包装中储存并分装10-mg片剂，防止受潮，并保持瓶子紧闭。 不要去除干燥剂。 TIVICAY片剂25毫克是浅黄色圆形薄膜包衣双凸面片剂，一面用“SV 572”压印，另一面用“SV 572”压印。 一瓶30片儿童安全封口。 NDC 49702-227-13。 TIVICAY片剂50mg为黄色圆形薄膜包裹双凸面片剂，一面装有“SV 572”，另一面装有“50”。 一瓶30片儿童安全封口。 NDC 49702-228-13。 在25°C（77°F）下储存; 允许偏离15°至30°C（59°至86°F）[参见USP受控室温]。 完整说明书附件： 1）：http://www.viivhealthcare.com/media/58599/us_tivicay.pdf 2）：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=63df5af3-b8ac-4e76-9830-2dbb340af922 Tivicay (Dolutegravir) for the Treatment of HIV-1 Infection Tivicay (dolutegravir) is an integrase inhibitor indicated for the treatment of the HIV-1 infection in adults and children aged 12 years and above. The drug was developed by ViiV Healthcare, a company established by GlaxoSmithKline, Pfizer and Shionogi. ViiV Healthcare submitted the new drug application (NDA) for Tivicay in December 2012. It received priority designation for Tivicay from the US Food and Drug Administration (FDA) in February 2013. The US FDA approved Tivicay 50mg tablets for treating HIV-1 in adults and children aged 12 years and above, and weighing at least 40kg, in August 2013. Tivicay received positive opinion for marketing authorisation from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of HIV in combination with other antiretroviral drugs in November 2013. Health Canada approved the drug in October 2013 and the Scottish Medicines Consortium (SMC) approved the drug for use within NHS Scotland in May 2014. ViiV Healthcare also submitted regulatory applications for Tivicay in Australia and Brazil. HIV-1 infection details Human immunodeficiency virus (HIV) is a lentivirus that delivers a significant amount of genetic information into the DNA of the host cell. HIV is responsible for causing acquired immune deficiency syndrome (AIDS), a fatal disease that destroys the immune system if not treated. It is categorised into two types, HIV-1 and HIV-2. HIV-1 is more virulent and infective than HIV-2. HIV is estimated to affect about 50,000 people in the US every year, according to the estimates by Centre for Disease Control and Prevention. The disease resulted in about 15,500 deaths in 2010. Tivicay’s (dolutegravir) mechanism of action Tivicay is an integrase inhibitor consisting of antiretroviral agent dolutegravir, which is used for treating HIV-1 in adults and children. The drug blocks HIV replication by averting the viral DNA from assimilating into the genetic material of human immune cells (T-cells). Tivicay is available in 50mg tablet form for oral administration. Clinical trials on Tivicay (dolutegravir) The marketing application submitted to the FDA was based on four Phase III clinical trials which were conducted on more than 2,557 patients who included HIV affected adults and children aged 12 years and above. Patients were treated with once-daily Tivicay-based regimen, compared to twice-daily raltegravir and another where the regimen of once-daily Tivicay and abacavir / lamivudine was compared to once-daily Atripla, a fixed-dose combination of efavirenz, emtricitabine and tenofovir. The results of the four Phase III studies showed that patients treated with Tivicay regimens were effective in reducing viral loads. The first Phase III clinical trial on Tivicay was known as SPRING-2 study. It evaluated once-daily Tivicay versus twice-daily raltegravir. It enrolled 822 HIV infected patients and was conducted for 48 weeks. Results of the first study after 48 weeks demonstrated that patients who were administered with regimen containing Tivicay were virologically suppressed by 88% when compared to 86% for the regimen containing raltegravir. The study showed that the tolerability of Tivicay was same as that of raltegravir. The second Phase III clinical trial was known as SINGLE study. It enrolled 833 patients with HIV infection. It evaluated once-daily Tivicay plus abacavir / lamivudine versus the single tablet regimen Atripla. The study was conducted for 48 weeks. Results of the second study showed that patients who were administered with regimen containing Tivicay were virologically suppressed by 88%, as compared to 81% for the regimen containing Atripla. The third Phase III clinical trial, known as the SAILING study, enrolled 719 HIV patients who failed on current therapy but not treated with an integrase inhibitor. The study evaluated once-daily Tivicay versus twice-daily raltegravir for 24 weeks. The results of the third study showed that at week 24, the patients treated with Tivicay regimen were virologically suppressed by 79% when compared to 70% in raltegravir-administered patients. The overall tolerability in Tivicay patients was similar to that of raltegravir patients. The fourth Phase III study known as VIKING-3 study evaluated twice-daily Tivicay. It enrolled 183 HIV patients with who were resistant to multiple classes of HIV medicines, including integrase inhibitors such as raltegravir or elvitegravir. The study results demonstrated that HIV RNA levels declined by 1.4 log10 c/mL after seven days of treatment. It also showed that participants who were subsequently virologically suppressed included 63% with Tivicay to their background regimen at week 24. The study, however, observed poor virologic response in subjects treated with Tivicay twice daily dose. Marketing commentary for ViiV Healthcare’s Tivicay Tivicay is marketed in the US by ViiV Healthcare and manufactured by GlaxoSmithKline (GSK). The sales of Tivicay are expected to reach about $900m by 2017 in the US, according to Thomson Reuters’ estimates. Other drugs approved for the treatment of HIV-1 include Sustiva (Efavirenz) developed by Bristol-Myers Squibb (BMS) and DuPont Merck, Stribild manufactured by Gilead Sciences and Japan Tobacco (JT), Truvada developed by Gilead Sciences, and Eviplera manufactured by Gilead Sciences International and Tibotec. ViiV HIV新药Tivicay获加拿大批准 2013年11月6日，葛兰素史克（GSK）和辉瑞（Pfizer）合资公司ViiV Healthcare 11月4日宣布，HIV新药Tivicay（dolutegravir，50mg片剂）已获加拿大卫生部批准，该药为HIV整合酶链转移抑制剂，旨在与其他抗逆转录病毒药物联合用药，用于HIV-1成人感染者和体重大于40千克的12岁及以上儿童感染者的治疗。 此前，Tivicay于2013年8月12日获FDA批准，与其他抗逆转录病毒制剂联合用于既往已治疗过、或初治HIV-1成人和12岁及以上体重至少40千克儿童感染者。 支持Tivicay新药申请的数据，包括多个非临床研究、临床药理学研究、以及4个关键性III期临床试验的数据。 Tivicay的服用，无需药代动力学助推剂，可空腹或与食物一起服用，并且可在一天的适合时间服用。 关于III期临床项目： SPRING-2：在822例HIV感染者中开展，评价了每天1次Tivicay与每天2次raltegravir（拉替拉韦）与一种固定剂量双NRTI疗法联合治疗的疗效。48周时，含Tivicay方案有88%的患者实现病毒学抑制（HIV-1 RNA<50 c/ml），含raltegravir方案为86%，达到了10%的非劣性标准。 SINGLE：在833例初治HIV感染者中开展，评价了每天1次Tivicay+阿巴卡韦/拉米夫定相对于单一片剂Atripla的疗效。48周时，含Tivicay方案有88%的患者实现病毒学抑制（HIV-1 RNA<50 c/ml），Atripla方案为81%，数据具有统计学显着差异。Tivicay方案组有2%患者因不良事件中止治疗，Atripla方案组为10%。 SAILING：在719例经当前疗法治疗失败但未使用整合酶抑制剂治疗的患者中开展，评价了每天1次Tivicay和每天2次raltegravir（拉替拉韦）结合一种背景方案（2种制剂，其中至少1种完全活性剂）的疗效。24周时，含Tivicay方案有79%的患者实现病毒学抑制（HIV-1 RNA<50 c/ml），含raltegravir方案为70%，数据具有统计学显着差异。 VIKING-3：在183例正在接受治疗、且HIV已对数类HIV药物（包括整合酶抑制剂雷特格韦和/或elvitegravir）的成人感染者中开展。该项研究中，背景方案中添加Tivicay治疗7天后，HIV RNA水平下降达1.4 log10 c/ml。24周时，添加Tivicay方案有63%的患者实现病毒学抑制（HIV-1 RNA<50 c/ml）。 批准Tivicay用于12岁及以上、体重至少40千克儿童的适应症，是基于一项多中心、开发标签试验的安全性、药代动力学、药效评价数据。该项研究在既往未接受过整合酶抑制剂治疗的患者中开展。 Dolutegravir是日服一次的药物，在III期临床试验中表现强劲，达到了与默沙东（Merck & Co）HIV/AIDS药物Isentress相匹敌的疗效。Isentress日服2次，这2者均为HIV整合酶的抑制剂，这是一类对抗HIV/AIDS的新型药物，能够阻止HIV病毒进入细胞。