HIV-1

bictegravir (BIC) 抑制链转移活性，IC50 为 7.5± 0.3 nM。 bictegravir 的 IC50 为 241±51 nM，对 HIV-1 IN 3'-加工活性的抑制作用比对链转移活性的抑制作用弱得多。与模拟处理的对照相比，bictegravir 使 2-LTR 环的积累增加了大约五倍，并将感染细胞中真实整合产物的数量减少了 100 倍。bictegravir 的 EC50 分别为 1.5 和 2.4 nM，有效抑制 MT-2 和 MT-4 细胞中的 HIV-1 复制。 bictegravir 的 EC50 分别为 1.5±0.3 nM 和 6.6±4.1 nM，在原代 CD4+ T 淋巴细胞和单核细胞衍生的巨噬细胞中表现出强大的抗病毒作用。这些值与 T 细胞系中观察到的值一致。

HIV-1 IIIb 在 MT-2 细胞上于 37°C 下批量培养 3 小时，细胞密度为 2×106 个细胞/mL。将 Bictegravir (BIC) 或 DMSO（模拟处理对照）给予感染的 MT-2 细胞，其最终浓度至少是每种药物抗病毒 50% 有效浓度 (EC50) 的 20 倍。收集细胞以获得总 DNA将这些板在 37°C 下孵育 12 小时（用于后期逆转录产物定量）或 24 小时（用于 2-LTR 环和 Alu-LTR 产物定量）后进行分离。使用 DNA 微型试剂盒，从每个孔中提取 DNA 并收集为 100 μL 洗脱液。每个样本中的宿主珠蛋白基因水平用于标准化 TaqMan 实时 PCR 定量的 2-LTR 连接点（2-LTR 环）、晚期逆转录产物和整合连接点 (Alu-LTR)[1]。

在批量培养中，MT-2 细胞在 37°C 下用 HIV-1 IIIb 感染 3 小时，细胞密度为 2×106 个细胞/mL。将 Bictegravir (BIC) 或 DMSO（模拟处理对照）给予感染的 MT-2 细胞，其最终浓度至少是每种药物抗病毒 50% 有效浓度 (EC50) 的 20 倍。将这些板在 37°C 下孵育 12 小时（用于后期逆转录产物定量）或 24 小时（用于 2-LTR 环和 Alu-LTR 产物定量）后，收获细胞以进行总 DNA 分离。使用 DNA 微型试剂盒，从每个孔中提取 DNA 并收集为 100 μL 洗脱液。每个样本中的宿主球蛋白基因水平作为 TaqMan 实时 PCR 定量 2-LTR 连接（2-LTR 环）、晚期逆转录产物和整合连接（Alu-LTR）的标准[1]。

Absorption, Distribution and Excretion
Bictegravir is rapidly absorbed within the body. Tmax= 2.0-4.0h
BIC is mainly eliminated through UGT1A1 glucuronidation and CYP3A4 oxidation, equally. About 1% of the bictegravir dose is excreted in the urine, unchanged.
0.2 L/Kg in humans
Bictegravir is mainly cleared by the kidneys. Those with renal clearance <30 should not take bictegravir [FDA LABEL]

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Metabolism / Metabolites
In a 10-day dose-ranging study, monotherapy (5 mg to 100 mg) once daily in adults who were not previously treated with bictegravir, the median half-life of BIC ranged from 15.9 h - 20.9 h. Bictegravir is metabolized in the liver and kidneys. CYP3A4 and UGT1A are the primary enzymes involved in the metabolism of bictegravir. Administration of bictegravir is not advised in patients with renal creatinine clearance of <30 mL/min and patients with hepatic disease [FDA LABEL].

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Biological Half-Life
Half-life is 17.3 hours.

Hepatotoxicity
In large clinical trials, therapy with bictegravir combined with emtricitabine and tenofovir alafenamide was associated with alanine aminotransferase (ALT) elevations (above 1.5 times ULN) in 11% patients, but these rates were similar to those in comparator groups (12% to 15%) receiving matched background optimized antiretroviral therapy without bictegravir. Elevations above 5 times ULN occurred in only 1.4% of bictegravir vs 0.9% to 1.3% of control comparator arm subjects. The elevations were not associated with clinical symptoms and generally did not require dose modification. In addition, there were no instances of acute hepatocellular liver injury with jaundice. The product label for bictegravir mentions acute exacerbations of hepatitis B and hepatic failure as potential adverse reactions when bictegravir with emtricitabine and tenofovir is discontinued. This adverse reaction can occur upon discontinuation of any antiretroviral regimen with concurrent activity against HBV and represents the effects of tenofovir and emtricitabine. Nevertheless, since its approval and its more widescale use, there have been no published reports of clinically apparent cases of liver injury or exacerbation of hepatitis B convincingly attributed to bictegravir.
Likelihood score: E* (unproven but suspected potential cause of liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal bictegravir 50 mg once daily produce low levels in milk and infant serum. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
> 99 % bound to human plasma Blood to plasma ratio: 0.64

[1]. Antimicrob Agents Chemother.2016 Nov 21;60(12):7086-7097.

Description
Bictegravir is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxylic acid with the amino group of 2,4,6-trifluorobenzylamine. It is a second-generation integrase strand transfer inhibitor (INSTI) and used (as its sodium salt) for the treatment of HIV-1. It has a role as a HIV-1 integrase inhibitor. It is a monocarboxylic acid amide, a secondary carboxamide, a trifluorobenzene and an organic heterotetracyclic compound. It is a conjugate acid of a bictegravir(1-).
Bictegravir is a recently approved investigational drug that has been used in trials studying the treatment of HIV-1 and HIV-2 infection. It has been approved for HIV-1 monotherapy combined with 2 other antiretrovirals in a single tablet.
Bictegravir is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor, the fourth in this class of agents that target the viral integrase. Bictegravir is used only in combination with other antiretroviral agents in the treatment of HIV infection and it has had limited use. Bictegravir 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.
Bictegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), that is used to treat HIV infection. Upon oral administration, bictegravir inhibits the strand transfer activity of HIV-1 integrase, an HIV-1 coded enzyme that is necessary for viral replication. Inhibition of integrase prevents the integration of linear HIV-1 DNA into host genomic DNA.

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Drug Indication
Bictegravir is indicated in the management of HIV-1 infection in patients not previously treated with antiretroviral therapy. Additionally, Bictegravir is indicated in the management of HIV-1 infection in patients who are virologically suppressed (HIV-1 RNA <50 c/mL) on a regular antiretroviral regimen for a minimum of three months without a history of failure in treatment and no known factors associated with the resistance to the individual components of the medication. It is used in combination with tenofovir and emtricitabine.
FDA Label

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Mechanism of Action
This single dose medication inhibits the strand transfer of viral DNA into the human genome, preventing HIV-1 virus replication and propagation. In vitro, bictegravir has shown powerful antiviral activity against HIV-2 and various subtypes of HIV-1. It has shown synergistic effects when combined with other ARVs, including tenofovir alafenamide (TAF), emtricitabine (FTC), and darunavir (DRV). The three components of the first USA approved medication ( trade name: Biktarvy ) are as follows: Bictegravir: integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme necessary for viral replication. Inhibition of the integrase enzyme prevents the integration of HIV-1 into host DNA, blocking the conversion of the HIV-1 provirus and progression of the virus [FDA LABEL]. Emtricitabine: FTC, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine is phosphorylated to form emtricitabine 5'-triphosphate intracellularly. This metabolite inhibits the activity of human immunodeficiency virus (HIV) reverse transcriptase by competing with the substrate deoxycytidine 5'-triphosphate and by incorporating itself into viral DNA preventing DNA chain elongation [FDA LABEL]. Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2′-deoxyadenosine monophosphate analog). Plasma exposure to TAF leads to leakage into cells and then TAF is intracellularly converted to tenofovir by hydrolysis by cathepsin. Tenofovir is subsequently phosphorylated by cellular kinases to the metabolite tenofovir diphosphate, which is the active form of the drug. Tenofovir diphosphate inhibits HIV-1 replication by incorporating into viral DNA by the HIV reverse transcriptase, resulting in DNA chain-termination. Tenofovir diphosphate also weakly inhibits mammalian DNA polymerases [FDA LABEL].

C21H18F3N3O5

449.37

449.119

C, 56.13; H, 4.04; F, 12.68; N, 9.35; O, 17.80

1611493-60-7

Bictegravir sodium;1807988-02-8;Bictegravir-15N,d2

90311989

Solid powder

1.62±0.1 g/cm3

682.5±55.0 °C at 760 mmHg

366.6±31.5 °C

0.0±2.2 mmHg at 25°C

1.664

-1.26

99.2

2

9

3

32

912

3

FC1C=C(C=C(C=1CNC(C1C(C(=C2C(N3[C@@H](CN2C=1)O[C@@H]1CC[C@H]3C1)=O)O)=O)=O)F)F

SOLUWJRYJLAZCX-LYOVBCGYSA-N

InChI=1S/C21H18F3N3O5/c22-9-3-14(23)12(15(24)4-9)6-25-20(30)13-7-26-8-16-27(10-1-2-11(5-10)32-16)21(31)17(26)19(29)18(13)28/h3-4,7,10-11,16,29H,1-2,5-6,8H2,(H,25,30)/t10-,11+,16+/m0/s1

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : 83.3 ~90 mg/mL ( 185.37 ~200.27 mM）

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.56 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 2 中的溶解度: ≥ 2.5 mg/mL (5.56 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 3 中的溶解度: ≥ 2.5 mg/mL (5.56 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 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: ≥ 2.5 mg/mL (5.56 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 5 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (5.56 mM)

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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。