HIV integrase strand transfer (IC50 = 2.7 nM)

Dolutegravir (S/GSK1349572) 在 PBMC 中针对 HIV-1 的 EC50 为 0.51 nM，在 MT-4 细胞中为 0.71 nM，在假型自失活病毒 (PHIV) 测定中为 2.2 nM。在增殖的 IM-9、U-937、MT-4 和 Molt-4 细胞中，多替拉韦的 50% 细胞毒性浓度 (CC50) 依次为 4.8、7.0、14 和 15 μM。未刺激和刺激的 PBMC 中的 CC50 值依次为 189 μM 和 52 μM。多替拉韦针对 PBMC 中 HIV-1 的 0.51 nM EC50 表明需要至少 9,400 的基于细胞的治疗指数[1]。

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S/GSK1349572是下一代HIV整合酶（IN）抑制剂，旨在以低毫克每日一次的剂量提供强效抗病毒活性，无需药代动力学（PK）增强剂。此外，S/GSK1349572显示出对临床相关In突变病毒的活性，并有可能成为抵抗的高遗传屏障。S/GSK1349572是一种双金属结合的HIV整合酶链转移抑制剂，其作用机制是通过体外整合酶测定、耐药性传代实验、对其他类抗HIV药物耐药的病毒株的活性以及细胞机制测定建立的。在多种细胞抗病毒检测中，S/GSK1349572以低纳摩尔或亚纳摩尔效力抑制HIV复制，选择性指数为9400。外推至100%人血清的蛋白质调整半最大有效浓度（PA-EC（50））为38 nM。当病毒在S/GSK1349572存在下传代时，没有选择高抗性突变体，但在整合酶活性位点附近鉴定出影响EC（50）低倍变化（FC）（高达4.1倍）的突变。S/GSK1349572显示出对含有拉替拉韦抗性特征突变Y143R、Q148K、N155H和G140S/Q148H（FC分别为1.4、1.1、1.2和2.6）的定点分子克隆的活性，而这些突变体导致拉替拉威EC（50）中的FC很高（11至>130倍）。当S/GSK1349572与具有代表性的经批准的抗逆转录病毒药物联合使用时，观察到相加或协同作用；未见拮抗作用。这些发现表明，S/GSK1349572将被归类为整合酶抑制剂类的下一代药物，其耐药性特征与第一代整合酶抑制剂明显不同[1]。

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Raltegravir（RAL）和相关的HIV-1整合酶（IN）链转移抑制剂（INSTIs）在体外有效阻断病毒复制，抑制患者的病毒血症。这些小分子与IN活性位点结合，使其与病毒DNA 3'端的脱氧腺苷脱离。对RAL高度耐药的病毒株的出现强调了开发具有改善耐药性的INSTIs的迫切需要。在此，我们表明候选的第二代药物多替拉韦（DTG，S/GSK1349572）有效地抑制了一组对第一代INSTIs耐药的HIV-1 IN变体。为了阐明DTG对RAL抗性IN增强效力的结构基础，我们确定了与该化合物结合的野生型和突变型原型泡沫病毒内吞体的晶体结构。DTG的整体IN结合模式与三环羟基吡咯MK-2048的结合模式非常相似。第二代INSTI在IN活性位点内占据几乎相同的物理空间，并与催化核心结构域的β4-α2环接触。与RAL和其他INSTI相比，连接金属螯合核心和DTG卤代苄基的延伸接头区域使其能够更深入地进入被置换的病毒DNA碱基腾出的口袋，并与病毒DNA进行更密切的接触。此外，我们的结构表明，DTG能够微妙地调整其位置和构象，以应对RAL抗性In活性位点的结构变化[2]。

在大鼠（0.23 mL/min/kg）和猴子（2.12 mL/min/kg）中，单次静脉（IV）剂量多替拉韦后的血浆清除率较低。大鼠和猴子的半衰期均约为 6 小时，且稳态分布容积 (VSS) 较小。当以溶液形式口服给一只雄性猴子和五只禁食的大鼠时，多替拉韦具有高生物利用度并快速吸收（分别为 75.6% 和 87.0%）。给非禁食大鼠口服高达 250 mg/kg 的混悬剂和非禁食猴子高达 50 mg/kg 的混悬液后，多替拉韦暴露（Cmax 和 AUC）随着剂量的增加而增加，但增加幅度小于比例[3 ]。

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1.多替拉韦是一种未经强化的HIV-1整合酶抑制剂，在大鼠和猴子体内的血浆清除率较低（分别为0.23和2.12 mL/min/kg），分布体积也较低（各自为0.1和0.28 L/kg），终末消除半衰期约为6小时。多替拉韦可从口服溶液中快速吸收，在大白鼠和猴子体内具有较高的生物利用度（分别为75.6%和87.0%），但以混悬剂形式给药时溶解度或溶解速率有限。2.多乐替拉韦在大鼠和猴子体内与血清蛋白高度结合（>99%），与人类血浆和血清蛋白的结合相似。放射性与所有物种的血浆和血液细胞成分有关。3.大鼠口服给药后，[（14）C]多替拉韦相关放射性分布到大多数组织，部分原因是高渗透性；然而，由于血浆蛋白结合率高，组织与血液的比率低。在小鼠、大鼠和猴子中，吸收的剂量被广泛代谢并分泌到胆汁中，大部分施用的放射性物质在24小时内通过粪便消除。多替拉韦的主要代谢途径是通过形成醚葡糖苷酸。其他生物转化途径：苄基氧化，然后水解成N-脱烷基产物，葡萄糖偶联，氧化脱氟和谷胱甘肽偶联[3]。

体外链转移测定。如前所述（5），在使用重组HIV整合酶的链转移测定中测量S/GSK1349572和其他INI的抑制能力。通过在37°C下将2μM纯化的重组整合酶与0.66μM生物素化的供体DNA-4 mg/ml链亲和素包被的SPA珠在25 mM吗啉丙磺酸钠（MOPS）（pH 7.2）、23 mM NaCl和10 mM MgCl2中孵育5分钟，形成整合酶和生物素化预处理的供体DNA-链亲和素-包被的闪烁邻近测定（SPA）珠的复合物。将这些珠子向下旋转，并与稀释的INIs在37°C下预孵育60分钟。然后，加入3H标记的靶DNA底物，得到最终浓度为7nM的底物，并将链转移反应混合物在37°C下孵育25至45分钟，这允许供体DNA向放射性标记靶DNA的链转移线性增加。使用Wallac MicroBeta闪烁板读取器[1]读取信号。

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PHIV检测。[1]
使用自灭活PHIV慢病毒载体在单轮试验中测量化合物的抗病毒活性。CIP4细胞（2×104个细胞/孔）感染PHIV，足以在检测中产生约50000个相对光单位。将感染的细胞加入96孔、黑色、透明的底板中，加入不同浓度的Dolutegravir (GSK1349572)，孵育2天。使用Steady-Glo试剂在光度计中测量萤光素酶活性。

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人血清和血清蛋白的影响。[1]
在PHIV和MT-4检测系统中评估了人血清白蛋白（HSA）（20或40 mg/ml）、α1-酸性糖蛋白（AAG）（2 mg/ml）和人血清（HS）（使用高达30%或50%，外推至100%）对Dolutegravir (GSK1349572)抗病毒活性的影响。为了评估蛋白质结合的影响，如前所述，在MT-4细胞中的HIV复制试验中加入不同浓度的人血清来测试抗病毒活性。通过将PBMC中的EC50乘以倍数偏移值来估算蛋白质调整的半最大有效浓度（PA-EC50）。

MT-4细胞的抗病毒检测。[1]
以5×105或6×105/ml的密度指数生长的MT-4细胞以0.001的病毒感染倍数或4至10的50%组织培养感染剂量感染HIV-1菌株IIIB。然后在不同浓度的化合物存在下将细胞等分到96孔板中。孵育4或5天后，通过细胞活力测定法测定抗病毒活性，所述细胞活力测定用CellTiter-Glo发光试剂测量生物发光，或用黄色四唑啉MTT试剂[3-（4,5-二甲基-2-噻唑基）-2,5-二苯基四唑啉溴化物]测量560和690nm处的吸光度

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PBMC中的抗病毒检测。[1]
在一个96孔培养板中，PHA和IL-2刺激的PBMC（4×105/孔）与一种化合物预孵育1小时，而HIV-1菌株Ba-L在第二个培养板中与相同的化合物混合。然后将Ba-L复合物混合物的等分试样转移到PBMC复合物混合物中并孵育7天。孵育后，如前所述，通过掺入[甲基-3H]dTTP来测定上清液的逆转录酶（RT）活性，以测量病毒复制

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细胞毒性测定。[1]
用S/GSK1349572在增殖的人白血病和淋巴瘤细胞系（IM-9、U-937、MT-4和Molt-4）以及刺激和未刺激的人PBMC中进行体外生长抑制（细胞毒性）研究。通过使用CellTiter-Glo萤光素酶试剂来量化ATP水平，以测量化合物抑制细胞生长的能力，作为化合物的细胞毒性潜力的指标

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机制细胞研究。[1]
为了确定S/GSK1349572是否通过整合酶抑制机制在细胞测定中抑制HIV复制，使用定量PCR方法在单轮感染测定中测量对MT-4细胞中HIV NL432 DNA物种合成的影响。如前所述，在INI或NNRTI存在下，进行定量PCR分析以测量MT-4细胞中HIV DNA物种的合成，并进行微小的修饰。简言之，用NL432质粒转染293T细胞以产生感染性病毒，并通过0.45μm孔径的过滤器过滤上清液，并用DNA酶I处理。将MT-4细胞用HIV-1 NL432感染1小时，用化合物的稀释液孵育，并在孵育6或18小时后收集。将所有细胞与0.5μM利托那韦一起孵育，以将HIV复制限制在单个周期内。通过培养样品6小时进行总DNA PCR以检测晚期RT产物。通过培养样品18小时进行嵌套Alu PCR以检测整合的前病毒和2-LTR PCR以检测2-LTR环。使用ABI Prism 7900HT-3序列检测系统分析反应产物。

For rat and monkey PK studies, Dolutegravir is administered as the free acid or the sodium salt. All doses are presented in terms of the free acid. Dolutegravir is administered by intravenous (IV) short-term (within 2 min) bolus (1 mg/kg) to three male rats and two male monkeys. For single oral administration, Dolutegravir as a solution (5 mg/kg) is administered to three fasted male rats and two fasted male monkeys. Dolutegravir is administered as single oral doses of 5, 50, 100, and 250 mg/kg to non-fasted male rats (n=2/dose level) and 3, 10, and 50 mg/kg to non-fasted female monkeys. For intravenous administration, blood samples are collected from rats (0.2 mL via jugular vein cannula) and monkeys (approximately 0.2 or 0.5 mL via saphenous vein in a hindlimb) into Na2EDTA-treated syringes at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h. For oral administration, samples are collected at 0.25 (rats only), 0.5, 1, 2, 4, 6 [rats (solution and suspension) and monkey (solution only)], 8, and 24 h. Following collection, the blood is immediately put on wet ice and then centrifuged within an hour at 1740 g for 10 min at 4°C to obtain plasma. All samples are stored at approximately -20°C or colder prior to analysis by using a method based on protein precipitation and LC-MS/MS analysis.[1]

2.7 mg/kg/day; administrated orally for two weeks.

C57BL/6 mice

Absorption, Distribution and Excretion
When 50 mg of dolutegravir once daily was orally administered to HIV-1 infected adults, the AUC, Cmax, and Cmin is 53.6 mcg h/mL, 3.67 mcg/mL, and 1.11 mcg/mL, respectively. The peak plasma concentration was observed 2 to 3 hours post-dose. Steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1.2 to 1.5. When 50 mg once daily is given to pediatric patients (12 to < 18 years and weighing ≥40 kg) the Cmax, AUC, and C24 is 3.49 mcg/mL, 46 mcg.h/mL, and 0.90 mcg/mL respectively.
When a single oral dose of dolutegravir is given, nearly all complete dose is recovered in a proportion of 53% excreted unchanged in the feces and 31% excreted in urine. The renal eliminated recovered dose consists of ether glucuronide of dolutegravir (18.9%), a metabolite formed by oxidation at the benzylic carbon (3.0%), a hydrolytic N-dealkylation product (3.6%) and unchanged drug (< 1%).
The administration of a dose of 50 mg of dolutegravir presents an apparent volume of distribution of 17.4 L. The median dolutegravir concentration in CSF was 18 ng/mL after 2 weeks of treatment.
The apparent clearance rate of dultegravir is 1.0 L/h.
... After a single oral dose of [14C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (<1% of the dose).
Dolutegravir is highly bound (=98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.
Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-8) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.
Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5. Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P-glycoprotein substrate in vitro. The absolute bioavailability of dolutegravir has not been established.

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Metabolism / Metabolites
Dolutegravir is highly metabolized through three main pathways and it forms no long-lived metabolites. The first pathway is defined by the glucuronidation by UGT1A1, the second pathway by carbon oxidation by CYP3A4 and the third pathway is what appears to be a sequential oxidative defluorination and glutathione conjugation. The main metabolite found in blood plasma is the ether glucuronide form (M2) and its chemical properties disrupt its ability to bind metal ions, therefore, it is inactive.
Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. ... ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). ...

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Biological Half-Life
The half-life of dolutegravir is 14 hours.
Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L/h based on population pharmacokinetic analyses.

Interactions
Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.
Coadministration of TIVICAY with dofetilide is contraindicated due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.

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Hepatotoxicity
In large clinical trials, therapy with dolutegravir was associated with alanine aminotransferase (ALT) elevations of greater than 3 times the upper limit of normal (ULN) in 2% to 5% of patients, but these rates were similar to those in comparator groups receiving matched background optimized antiretroviral therapy without dolutegravir. These elevations were not associated with clinical symptoms and generally did not require dose modification. A few instances of acute liver injury with jaundice were described in the registration trials for dolutegravir which occurred in association with hypersensitivity reactions and resolved with drug discontinuation. The clinical features of these cases were not provided and their association with dolutegravir as opposed to the concurrent antiretroviral agents was not fully established. Since its approval and more wide spread use, however, several case reports of acute hepatitis attributable to dolutegravir have appeared. The latency to onset varried from 1 to 8 months and the pattern of serum enzyme elevations was hepatocellular. Immunoallergic and autoimmune features were not present. At least one published case resulted in acute liver failure and need for liver transplanation. The product label for dolutegravir mentions hepatitis and hepatic failure as potential adverse reactions and states that patients with hepatitis B or C coinfection are susceptible to worsening or flares of hepatitis with initiation of dolutegravir therapy, perhaps as a consequence of immune reconstitution syndrome. Monitoring of liver tests is recommended in patients starting regimens that include dolutegravir. Likelihood score: D (possible cause of clinically apparent liver injury).

Protein Binding
Dolutegravir is highly protein bound to human plasma proteins reaching a percentage 98.9% of the administered dose.

Human Toxicity Excerpts
/HUMAN EXPOSURE STUDIES/ Dolutegravir is primarily metabolized and eliminated by the liver. In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment. US Natl Inst Health; DailyMed. Current Medication Information for TIVICAY (dolutegravir sodium) tablet, film coated TIVICAY (dolutegravir) Tablets for Oral Use (Initial U.S. Approval: 2013). Available from, as of November 22, 2013:

Non-Human Toxicity Excerpts /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg/kg, and rats were administered doses of up to 50 mg/kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14-fold higher than those in humans at the recommended dose of 50 mg twice daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10-fold and 15-fold higher in males and females, respectively, than those in human at the recommended dose of 50 mg twice daily.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg/kg daily, approximately 0.4 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg/kg. US Natl Inst Health; DailyMed. Current Medication Information for TIVICAY (dolutegravir sodium) tablet, film coated TIVICAY (dolutegravir) Tablets for Oral Use (Initial U.S. Approval: 2013). Available from, as of November 22, 2013:

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg/kg daily, approximately 27 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity. US Natl Inst Health; DailyMed. Current Medication Information for TIVICAY (dolutegravir sodium) tablet, film coated TIVICAY (dolutegravir) Tablets for Oral Use (Initial U.S. Approval: 2013). Available from, as of November 22, 2013:

/GENOTOXICITY/ Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

[1]. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011 Feb;55(2):813-21.

[2]. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72.

[3]. The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys. Xenobiotica. 2015 Jan;45(1):60-70.

Therapeutic Uses
HIV Integrase Inhibitors
The recommended dose of TIVICAY in pediatric patients aged 12 years and older and weighing at least 40 kg is 50 mg administered orally once daily. If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are coadministered, the recommended dose of TIVICAY is 50 mg twice daily. Safety and efficacy of TIVICAY have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).
TIVICAY (dolutegravir) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children aged 12 years and older and weighing at least 40 kg. The following should be considered prior to initiating treatment with TIVICAY: Poor virologic response was observed in subjects treated with TIVICAY 50 mg twice daily with an integrase strand transfer inhibitor (INSTI)-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R.
Renal clearance of unchanged drug is a minor pathway of elimination for dolutegravir. In a trial comparing 8 subjects with severe renal impairment (CrCl <30 mL/min) with 8 matched healthy controls, AUC, Cmax, and C24 of dolutegravir were decreased by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. The cause of this decrease is unknown. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. No dosage adjustment is necessary for treatment-naive or treatment-experienced and INSTI-naive patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients requiring dialysis.
Dolutegravir is primarily metabolized and eliminated by the liver. In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment.

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Drug Warnings
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving TIVICAY.
Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed.
Dolutegravir (TIVICAY) should not be used with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
For more Drug Warnings (Complete) data for Dolutegravir (8 total), please visit the HSDB record page.

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Pharmacodynamics
HIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent reduction of antiviral activity with declines of HIV-1 RNA copies per ml. The antiviral response was maintained for 3 to 4 days after the last dose. The sustained response obtained in clinical trials indicates that dolutegravir has a tight binding and longer dissociative half-life providing it a high barrier to resistance. The combination therapy (ripivirine and dolutegravir) presented the same viral suppression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.

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Dolutegravir is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (4R,12aS)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid with the amino group of 2,4-difluorobenzylamine. Used (as its sodium salt) for treatment of HIV-1. It has a role as a HIV-1 integrase inhibitor. It is a monocarboxylic acid amide, an organic heterotricyclic compound, a secondary carboxamide and a difluorobenzene. It is a conjugate acid of a dolutegravir(1-).
Dolutegravir (brand names: Tivicay and Tivicay PD) is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in combination with:
Other HIV medicines in adults;
Other HIV medicines in children at least 4 weeks of age and older who weigh at least 6.6 lb (3 kg) and who meet specific requirements, as determined by a health care provider; or
Rilpivirine (brand name: Edurant) in adults to replace their current HIV medicines when their health care provider determines that they meet certain requirements.
Dolutegravir is always used in combination with other HIV medicines.
Dolutegravir is an HIV-1 integrase inhibitor that blocks the strand transfer step of the integration of the viral genome into the host cell (INSTI). The effect of this drug has no homology in human host cells, which gives it excellent tolerability and minimal toxicity. Dolutegravir was developed by ViiV Healthcare and FDA-approved on August 12, 2013. On November 21, 2017, dolutegravir, in combination with rilpivirine, was approved as part of the first complete treatment regimen with only two drugs for the treatment of adults with HIV-1 named Juluca.

Dolutegravir is a Human Immunodeficiency Virus Integrase Strand Transfer Inhibitor. The mechanism of action of dolutegravir is as a HIV Integrase Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor, and Organic Cation Transporter 2 Inhibitor.

Dolutegravir is a human immunodeficiency virus (HIV) integrase inhibitor, the third in this class of agents that target the viral integrase. Dolutegravir is used only in combination with other antiretroviral agents in the treatment of HIV infection, and it has had limited use. Dolutegravir is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of acute, clinically apparent liver injury.

Dolutegravir is an orally bioavailable integrase strand-transfer inhibitor (INSTI), with activity against human immunodeficiency virus type 1 (HIV-1) infection. Upon oral administration, dolutegravir binds to the active site of integrase, an HIV enzyme that catalyzes the transfer of viral genetic material into human chromosomes. This prevents integrase from binding to retroviral deoxyribonucleic acid (DNA), and blocks the strand transfer step, which is essential for the HIV replication cycle. This prevents HIV-1 replication.

DOLUTEGRAVIR is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2013 and is indicated for hiv infection and hiv-1 infection and has 7 investigational indications.

C20H19F2N3O5

419.38

419.129

C, 57.28; H, 4.57; F, 9.06; N, 10.02; O, 19.08

1051375-16-6

Dolutegravir sodium;1051375-19-9;Cabotegravir;1051375-10-0;Dolutegravir-d3;Dolutegravir-d5;2249814-82-0; 1051375-16-6 (free); 1051375-19-9 (sodium); 1357289-29-2 (RR-isomer); 1309560-49-3 (SR isomer)

54726191

White to off-white solid

1.53 g/cm3

669.0±55.0 °C at 760 mmHg

190-193ºC

358.4±31.5 °C

0.0±2.1 mmHg at 25°C

1.650

-1.32

104.36

2

8

3

30

829

2

FC1=CC(F)=C(C=C1)CNC(C2=CN(C3=C(C2=O)O)C[C@@]([H])(N4C3=O)OCC[C@H]4C)=O

RHWKPHLQXYSBKR-BMIGLBTASA-N

InChI=1S/C20H19F2N3O5/c1-10-4-5-30-15-9-24-8-13(17(26)18(27)16(24)20(29)25(10)15)19(28)23-7-11-2-3-12(21)6-14(11)22/h2-3,6,8,10,15,27H,4-5,7,9H2,1H3,(H,23,28)/t10-,15+/m1/s1

(4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.62 mg/mL (6.25 mM) (饱和度未知) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.96 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.96 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 4 中的溶解度: ≥ 2.5 mg/mL (5.96 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。