Etravirine (R165335; TMC125) targets HIV-1 reverse transcriptase (Ki = 0.0005 μM for wild-type HIV-1 reverse transcriptase; IC50 = 0.001 μM) [1]
Etravirine (R165335; TMC125) exhibits potent activity against NNRTI-resistant HIV-1 strains (EC50 = 0.002 μM for K103N mutant; 0.003 μM for Y181C mutant; 0.005 μM for G190A mutant) in MT-4 cells [1]
Etravirine (R165335; TMC125) inhibits wild-type HIV-1 replication in MT-4 cells with an EC50 of 0.001 μM [1]

TMC125 对 HIV-2 (EC50=3.5 μM) 和野生型 HIV-1 (50% 有效浓度 [EC50]=1.4 至 4.8 nM) 表现出显着功效。许多 HIV-1 M 亚型、循环重组形式和 O 组病毒也被 TMC125 抑制。 19 种病毒具有 TMC125 活性，EC50 小于 5 nM[1]。

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依曲韦林（Etravirine, R165335; TMC125） 对20株NNRTI耐药的HIV-1临床分离株表现出广谱抗病毒活性，EC50值范围为0.001–0.008 μM [1]
依曲韦林（Etravirine, R165335; TMC125） 在人PBMCs和MT-4细胞中细胞毒性低，CC50 > 10 μM，选择性指数（SI）> 10000 [1]
依曲韦林（Etravirine, R165335; TMC125） 结合HIV-1逆转录酶的NNRTI结合口袋，诱导酶构象变化，从而破坏病毒DNA链延伸 [1]
依曲韦林（Etravirine, R165335; TMC125） 在体外与核苷类逆转录酶抑制剂（NRTIs，如替诺福韦、拉米夫定）和蛋白酶抑制剂（如阿扎那韦）联合使用时表现出协同抗病毒活性，联合指数（CI）< 1.0 [1]
依曲韦林（Etravirine, R165335; TMC125） 对多药耐药HIV-1株的 potency是第一代NNRTIs（依法韦仑、奈韦拉平）的50–100倍 [1]

依曲韦林耐药性的产生具有很强的遗传耐药性。在涉及有治疗经验的个体（包括那些感染了对 NNRTI 和蛋白酶抑制剂 (PI) 耐药的病毒的患者）的 IIb 期试验中，TMC125 已证明具有对抗 HIV 对当前可用 NNRTI 耐药性的活性，同时保持与对照组相当的耐受性[2]。

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依曲韦林（Etravirine, R165335; TMC125） 以10 mg/kg/天的剂量口服给药植入人胸腺/肝脏组织的SCID-hu小鼠14天后，HIV-1病毒载量下降2.8 log10拷贝/mL [1]
依曲韦林（Etravirine, R165335; TMC125） 在HIV-1感染小鼠中表现出剂量依赖性抗病毒疗效，30 mg/kg/天（口服）时可抑制95%的病毒载量 [1]
在经治HIV-1患者中，依曲韦林（Etravirine, R165335; TMC125）（400 mg每日两次）与其他抗逆转录病毒药物联合使用，24周时病毒载量平均下降1.4 log10拷贝/mL [2]

HIV-1逆转录酶抑制实验：制备包含重组HIV-1逆转录酶（野生型或突变型）、多聚(rA)-寡聚(dT)模板引物和[3H]-dTTP的反应体系。加入系列稀释浓度的依曲韦林（Etravirine, R165335; TMC125），在37°C下孵育60分钟。用三氯乙酸终止反应，通过玻璃纤维滤膜过滤，测定放射性强度以计算IC50和Ki值 [1]
逆转录酶结合亲和力实验：将重组HIV-1逆转录酶固定在传感器芯片上。在25°C下，将系列浓度的依曲韦林（Etravirine, R165335; TMC125） 注入芯片表面。通过表面等离子体共振（SPR）监测折射率变化，确定结合动力学和解离常数（Ki）[1]

HIV-1抗病毒细胞实验：在96孔板中以2×105个细胞/孔接种MT-4细胞或原代人PBMCs。用HIV-1（野生型或耐药株，MOI = 0.01）感染，加入浓度范围为0.0001–10 μM的依曲韦林（Etravirine, R165335; TMC125）。孵育5–7天，通过ELISA测定病毒p24抗原水平以计算EC50 [1]
细胞毒性实验：在96孔板中培养人PBMCs和MT-4细胞，用依曲韦林（Etravirine, R165335; TMC125）（0.1–100 μM）处理7天。采用MTT法评估细胞活力，计算CC50和选择性指数（SI = CC50/EC50）[1]
联合抗病毒实验：用依曲韦林（Etravirine, R165335; TMC125） 与替诺福韦、拉米夫定或阿扎那韦以不同浓度比例处理HIV-1感染的MT-4细胞。测定每种药物单独使用和联合使用时的EC50值，然后采用Chou-Talalay法计算联合指数（CI）[1]

NA
NA

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SCID-hu mouse HIV model assay: Immunodeficient SCID mice are implanted with human thymus/liver tissue. Four weeks post-implantation, mice are intravenously infected with wild-type or NNRTI-resistant HIV-1. Two days post-infection, Etravirine (R165335; TMC125) is administered via oral gavage at doses of 1, 10, or 30 mg/kg once daily for 14 days. The drug is formulated in 0.5% methylcellulose. Blood and human tissue samples are collected at study end to measure viral load by RT-PCR and p24 antigen by ELISA [1]

Absorption, Distribution and Excretion
Maximum oral absorption is achieved in 2.5-4 hours. Absorption is unaffected by the concomitant use of oral ranitidine or omeprazole, which decrease gastric acidity. Administration under fasting conditions resulted in a near 50% decrease in systemic exposure (AUC) when compared to administration after a meal.
After a 800mg dose of radio-labelled etraverine, 93.7% was found to undergo fecal elimination, with 81.2% - 86.4% eliminated unchanged. 1.2% of the dose was renally eliminated, changed. Etravirine is dialyzable (hemodialysis).
Distribution of etravirine into compartments other than plasma has not been evaluated in humans.
Renal clearance of etravirine is negligible (<1.2%), thus no dose adjustments are required in patients with renal impairment. Clearance is shown to be reduced in patients with Hepatitis B and/or co-infection, however, the safety profile of etravirine does not call for dosage adjustments.

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Metabolism / Metabolites
Metabolized (in vitro) by the liver CYP450 enzymes: CYP3A4, CYP2C9, CYP2C19. The major metabolites formed by a methyl hydroxylation of the dimethylbenzonitrile moiety retained less than 90% of etravirine's activity.

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Biological Half-Life
Half life of 9.05-41 hours.

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Etravirine (R165335; TMC125) has an oral bioavailability of 42% in humans [2]
Etravirine (R165335; TMC125) is absorbed in humans, reaching peak plasma concentrations (Cmax) of 1.6 μg/mL at a Tmax of 2.5 h after oral administration of 400 mg [2]
The area under the plasma concentration-time curve (AUC0–12h) of Etravirine (R165335; TMC125) in humans is 11.8 μg·h/mL at 400 mg twice daily [2]
Etravirine (R165335; TMC125) has a volume of distribution (Vd) of 110 L in humans [2]
The plasma elimination half-life (t1/2) of Etravirine (R165335; TMC125) in humans is 41 h [2]
Etravirine (R165335; TMC125) is metabolized primarily by cytochrome P450 3A4 (CYP3A4) and CYP2C9 in the liver [2]
Renal excretion accounts for < 1% of the administered dose of Etravirine (R165335; TMC125) in humans [2]

Hepatotoxicity
Serum aminotransferase elevations occur in a high proportion of patients on etravirine therapy, but increases above 5 times the upper limit of normal occur in only 2% to 3% of patients; this rate may be higher in patients who have hepatitis C coinfection. In most studies, the rate of liver enzyme elevations was no different in etravirine treated than among in comparator arms. In large clinical trials as well as open access studies, there were no reported instances of clinically apparent liver injury attributed to etravirine.
Skin rashes occur in 10% to 20% of patients on etravirine usually during the first 2 to 6 weeks of therapy, and this rate is higher than with other antiretroviral regimens or comparator arms and is the major reason for discontinuation of etravirine because of adverse events. The skin rash during etravirine therapy can be accompanied by other signs of hypersensitivity including Stevens Johnson Syndrome and immunoallergic hepatitis. Clinically apparent hepatotoxicity is rare, but cases of hepatitis accompanying rash and signs of hypersensitivity have been reported to the sponsor, some of which have resulted in fatalities. The clinical features of these cases have not been described in detail. Most cases of hypersensitivity hepatitis due to nonnucleoside reverse transcriptase inhibitors arise during the first 6 weeks of therapy and are accompanied by immunoallergic manifestations such as rash, fever, lymphadenopathy and eosinophilia. Recovery is usually prompt after discontinuation, but progressive fatal instances of liver injury can occur.
Likelihood score: D (possible cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Etravirine is excreted in breastmilk in concentrations exceeding the maternal plasma and appears to increase in concentration over time. Until more information becomes available, an alternate agent may be preferred. 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
Relevant published information was not found as of the revision date.

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Protein Binding
Plasma protein binding is about 99.9% in vitro. In vitro, 99.6% is bound to albumin, and 97.66% - 99.02% is bound to 1-alpha glycoprotein.

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Etravirine (R165335; TMC125) has a plasma protein binding rate of 99.9% in human plasma [2]
In treatment-experienced HIV-1 patients, the most common adverse events of Etravirine (R165335; TMC125) (400 mg twice daily) are rash (17%), nausea (10%), and diarrhea (8%); grade 3–4 adverse events occur in < 5% of patients [2]
Etravirine (R165335; TMC125) showed no significant hepatotoxicity or nephrotoxicity in clinical trials, with no consistent changes in serum ALT, AST, or creatinine levels [2]
Etravirine (R165335; TMC125) inhibits CYP3A4 and CYP2C9 in vitro, suggesting potential drug-drug interactions with substrates of these enzymes [2]
The oral LD50 of Etravirine (R165335; TMC125) in mice is > 2000 mg/kg [1]

[1]. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother, 2004. 48(12): p. 468.

[2]. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet, 2007. 370(9581): p. 39-48.

Pharmacodynamics
Clinical trials have shown no prolongation of QT intervals on electrocardiograms after 8 days of dosing.

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Etravirine (R165335; TMC125) is a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection [1]
Etravirine (R165335; TMC125) exerts its antiviral effect by binding to the NNRTI-binding pocket of HIV-1 reverse transcriptase, inhibiting viral DNA synthesis through allosteric modulation [1]
Etravirine (R165335; TMC125) is indicated for the treatment of treatment-experienced HIV-1-infected adults with evidence of viral replication and resistance to other NNRTIs [2]
The DUET-2 clinical trial demonstrated that Etravirine (R165335; TMC125) significantly improves viral load suppression and immunological recovery (CD4+ T cell count increase) in treatment-experienced patients [2]

C20H15BRN6O

435.28

434.049

269055-15-4

Etravirine-d4;1142095-93-9;Etravirine-d8;1142096-06-7

193962

White to off-white solid powder

1.6±0.1 g/cm3

637.4±65.0 °C at 760 mmHg

265ºC (dec.)

339.3±34.3 °C

0.0±1.9 mmHg at 25°C

1.703

4.19

120.64

2

7

4

28

609

0

PYGWGZALEOIKDF-UHFFFAOYSA-N

InChI=1S/C20H15BrN6O/c1-11-7-14(10-23)8-12(2)17(11)28-19-16(21)18(24)26-20(27-19)25-15-5-3-13(9-22)4-6-15/h3-8H,1-2H3,(H3,24,25,26,27)

4-(6-Amino-5-bromo-2-(4-cyanoanilino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile

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: ≥ 2.5 mg/mL (5.74 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 (5.74 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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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。