Rilpivirine (R278474; TMC278) targets HIV-1 reverse transcriptase (Ki = 0.004 μM for wild-type HIV-1 reverse transcriptase) [1]
Rilpivirine (R278474; TMC278) inhibits wild-type HIV-1 reverse transcriptase with an IC50 of 0.015 μM, and exhibits potent activity against NNRTI-resistant strains (IC50 = 0.03 μM for K103N mutant, 0.04 μM for Y181C mutant) [2]
Rilpivirine (R278474; TMC278) shows antiviral activity against wild-type HIV-1 in MT-4 cells with an EC50 of 0.007 μM [2]

所有测试的单突变体和双突变体 (EC50=0.1-2.0 nM) 和野生型 HIV-1 (EC50=0.4 nM) 均对 R278474 的活性敏感[1]。 30 天内，R278474（10-5000 nM；30 天）在 1 μM 浓度下未显示任何野生型 HIV-1 突破的迹象[1]。在低于 1 nM 的 50% 抑制浓度 (EC50) 下，R278474 可抑制 81% 的临床分离株（约 1200 种重组临床分离株），在 EC50 低于 10 nM 时，可抑制 94%[1]。 TMC278 在 MT4 T 细胞中对 O 组分离株表现出纳摩尔 EC50 (2.88-8.45 nM)，对野生型 HIV-1 M 组分离株表现出亚纳摩尔 EC50 (0.07-1.01 nM)[2]。

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利匹韦林（Rilpivirine, R278474; TMC278） 对13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0.006–0.045 μM [2]
利匹韦林（Rilpivirine, R278474; TMC278） 在人PBMCs和MT-4细胞中细胞毒性低，CC50 > 10 μM，选择性指数（SI）> 1428 [2]
利匹韦林（Rilpivirine, R278474; TMC278） 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合成 [1]
利匹韦林（Rilpivirine, R278474; TMC278） 在体外与核苷类逆转录酶抑制剂（NRTIs，如替诺福韦、恩曲他滨）联合使用时表现出协同抗病毒活性，联合指数（CI）< 1.0 [2]
利匹韦林（Rilpivirine, R278474; TMC278） 在原代人CD4+ T细胞中抑制HIV-1复制，EC50为0.005 μM [2]
利匹韦林（Rilpivirine, R278474; TMC278） 对携带K103N、Y181C或G190A突变的NNRTI耐药HIV-1株的 potency是依法韦仑的10–30倍 [2]

用 R278474（10-160 mg/kg；口服 1 个月）治疗的大鼠没有表现出任何异常效应，但较高剂量水平下肝脏重量增加和物种特异性甲状腺肥大除外[1]。在大鼠中，R278474 (iv) 的消除半衰期为 4.4 小时至 31 小时。在狗中，暴露量 (AUCinf) 为每公斤 8.7 小时 (1.25 mg/kg)，在兔中为每公斤 1.4 小时 (1.25 mg/kg)，以及每公斤 44 小时 (1.25 mg/kg)[1]。在大鼠和狗中，R278474 (po) 的半衰期分别为 2.8 和 39 小时，口服生物利用度分别为 32% 和 31%[1]。

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利匹韦林（Rilpivirine, R278474; TMC278） 以10 mg/kg每日一次口服给药，治疗植入人胸腺/肝脏组织的SCID-hu小鼠14天后，HIV-1病毒载量下降2.3 log10拷贝/mL [2]
利匹韦林（Rilpivirine, R278474; TMC278） 在感染野生型HIV-1的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90%的病毒载量 [2]
利匹韦林（Rilpivirine, R278474; TMC278） 在SCID-hu小鼠模型中，停药后仍能维持病毒载量抑制达7天 [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利匹韦林（Rilpivirine, R278474; TMC278），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值 [2]
结合亲和力实验（SPR）：将重组HIV-1逆转录酶固定在传感器芯片上。在25°C下，将系列浓度的利匹韦林（Rilpivirine, R278474; TMC278） 注入芯片表面。监测折射率变化，以确定解离常数（Ki）和结合动力学 [1]
逆转录酶构象变化实验：将HIV-1逆转录酶与利匹韦林（Rilpivirine, R278474; TMC278） 孵育30分钟，然后加入NNRTI结合口袋特异性荧光探针。测量荧光强度以评估药物诱导的构象变化 [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CD4+ T细胞。用HIV-1感染（野生型MOI = 0.01，耐药株MOI = 0.05），并加入浓度范围为0.001–10 μM的利匹韦林（Rilpivirine, R278474; TMC278）。孵育5–7天，通过ELISA测定病毒p24抗原水平以计算EC50 [2]
细胞毒性实验：在96孔板中培养人PBMCs或MT-4细胞，加入利匹韦林（Rilpivirine, R278474; TMC278）（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）[2]
联合抗病毒实验：用利匹韦林（Rilpivirine, R278474; TMC278） 与替诺福韦或恩曲他滨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）[2]

Dissolved in PEG 400; 4 mg/kg ( rat); 1.25 mg/kg (other species); i.v. or p.o.
Sprague Dawley rat, beagle dog, white New Zealand rabbit, and cynomolgus monkey.

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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 HIV-1. Two days post-infection, Rilpivirine (R278474; TMC278) 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 [2]
Mouse pharmacokinetic assay: Male CD-1 mice (8–10 weeks old) receive oral Rilpivirine (R278474; TMC278) at 10 mg/kg, formulated in 0.5% methylcellulose. Blood samples are collected at 0.25, 0.5, 1, 2, 4, 8, and 24 h post-administration. Plasma is separated, and drug concentrations are measured by LC-MS/MS to determine PK parameters [2]

Absorption, Distribution and Excretion
Rilpivirine has a Tmax of 3-4 hours and has a mean AUC of 2235 ± 851 ng\h/mL. A 25mg dose reaches a Cmax of 247 ng/mL in healthy subjects and 138.6 ng/mL in patients with HIV-1.
Rilpivirine is 85% eliminated in the feces and 6.1% eliminated in the urine. 25% of a dose is recovered in the feces as the unchanged parent drug, while <1% of a dose is recovered in the urine as the unchanged parent drug.
In HIV-1 patients, the apparent volume of distribution in the central compartment was 152-173 L.
In HIV-1 patients, the apparent total clearance is estimated to be 6.89-8.66 L/h.
After a single oral dose, an average of 85% of the dose is eliminated in feces (75% as metabolites) and 6% is eliminated in urine (only trace amounts as unchanged rilpivirine).
It is not known whether rilpivirine is distributed into human milk; however, the drug is distributed into milk in rats.

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Metabolism / Metabolites
Rilpivirine is predominantly metabolized by CYP3A4 and CYP3A5 to the hydroxylated metabolites M1, M2, M3, and M4. UGT1A1 glucuronidates the M2 metabolite to form M6, UGT1A4 glucuronidates rilpivirine to form M5, and an unknown UGT glucuronidates the M4 metabolite to form M7.
Rilpivirine is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A.

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Biological Half-Life
Rilpivirine has a terminal half-life of 34-55 hours.
The terminal elimination half-life of rilpivirine is approximately 50 hours.

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Rilpivirine (R278474; TMC278) has an oral bioavailability of 60% in mice [2]
Rilpivirine (R278474; TMC278) is slowly absorbed in mice, reaching peak plasma concentrations (Cmax) of 1.2 μg/mL at a Tmax of 4 h after oral administration of 10 mg/kg [2]
The area under the plasma concentration-time curve (AUC0–24h) of Rilpivirine (R278474; TMC278) in mice is 12.8 μg·h/mL at 10 mg/kg oral dose [2]
Rilpivirine (R278474; TMC278) has a large volume of distribution (Vd = 8.5 L/kg) in mice, indicating extensive tissue penetration [2]
The plasma elimination half-life (t1/2) of Rilpivirine (R278474; TMC278) in mice is 12 h [2]
Rilpivirine (R278474; TMC278) is metabolized primarily by cytochrome P450 3A4 (CYP3A4) in the liver [2]
Renal excretion accounts for < 5% of the administered dose of Rilpivirine (R278474; TMC278) in mice [2]

Hepatotoxicity
Serum aminotransferase elevations occur in 25% or more of patients on rilpivirine therapy, but elevations above 5 times the upper limit of normal are uncommon, occurring in 1% to 4% of patients. The rate of serum aminotransferase elevations during rilpivirine therapy is higher in patients who are coinfected with hepatitis B or C [~10% have values greater than 5 times ULN]. The product label for rilpivirine induces a warning about hepatotoxicity particularly in patients with HBV or HCV coinfection and recommends monitoring for liver test abnormalities. During the first several years of wide spread clinical use of rilpivirine, a single case report of liver injury was published. The case was marked by prominent elevations in serum ALT and AST without jaundice arising within days of starting therapy and resolving rapidly upon stopping (Case 1). There was no rash, eosinophilia or other prominent immunoallergic features which are typical of the liver injury associated with nevirapine and efavirenz. Thus, clinically apparent hepatotoxicity due to rilpivirine may occur but is rare.
Liklihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal rilpivirine doses of 25 mg 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
Relevant published information was not found as of the revision date.

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Protein Binding
Rilpivirine is >99% bound to plasma protein, most commonly albumin.

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Interactions
Concomitant use of omeprazole and rilpivirine has resulted in decreased rilpivirine plasma concentrations and AUC. Concomitant use of other proton-pump inhibitors (e.g., esomeprazole, lansoprazole, pantoprazole, rabeprazole) also may result in decreased rilpivirine plasma concentrations. Concomitant use of rilpivirine and proton-pump inhibitors is contraindicated.
Concomitant use of famotidine and rilpivirine has resulted in decreased rilpivirine plasma concentrations and area under the concentration-time curve (AUC). Concomitant use of other histamine H2-receptor antagonists (e.g., cimetidine, nizatidine, ranitidine) also may result in decreased rilpivirine plasma concentrations. Rilpivirine and histamine H2-receptor antagonists should be used concomitantly with caution; histamine H2-receptor antagonists should be administered at least 12 hours before or at least 4 hours after rilpivirine.
Potential pharmacokinetic interaction with antacids such as aluminum hydroxide, calcium carbonate, or magnesium hydroxide (decreased plasma rilpivirine concentrations). Antacids and rilpivirine should be used concomitantly with caution; antacids should be administered at least 2 hours before or at least 4 hours after rilpivirine.
Rilpivirine is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A. Concomitant use with drugs that induce CYP3A may result in decreased plasma rilpivirine concentrations and may result in possible loss of virologic response and development of resistance to rilpivirine or the nonnucleoside reverse transcriptase inhibitor (NNRTI) class. Concomitant use with drugs that inhibit CYP3A may result in increased plasma rilpivirine concentrations. When the recommended rilpivirine dosage (25 mg once daily) is used, it is unlikely to have clinically important effects on the pharmacokinetics of drugs that are metabolized by CYP isoenzymes.

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Rilpivirine (R278474; TMC278) has a plasma protein binding rate of 99.7% in human plasma [2]
In mice, oral administration of Rilpivirine (R278474; TMC278) at 300 mg/kg/day for 28 days did not cause significant changes in body weight, hematological parameters, or liver/kidney function [2]
Rilpivirine (R278474; TMC278) showed no significant cytotoxicity in human hepatoma (HepG2) or renal proximal tubule (HK-2) cells at concentrations up to 100 μM [2]
Rilpivirine (R278474; TMC278) inhibits CYP3A4 in vitro, with an IC50 of 1.2 μM, suggesting potential drug-drug interactions with CYP3A4 substrates [2]
The oral LD50 of Rilpivirine (R278474; TMC278) in mice is > 2000 mg/kg [2]

[1]. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem. 2005 Mar 24;48(6):1901-9.

[2]. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother. 2010 Feb;54(2):718-27.

Therapeutic Uses
HIV Reverse Transcriptase/antagonists & inhibitors
Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (>/= 3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.

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Drug Warnings
Adverse effects of moderate or severe intensity and reported in 2% or more of patients receiving rilpivirine include depressive disorders, insomnia, headache, and rash. Increased serum AST and/or ALT concentrations (more than 2.5 times the upper limit of normal (ULN) were reported in 3-4% of patients receiving rilpivirine.
Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease since concentrations of the drug may be increased due to alterations in absorption, distribution, or metabolism.
Rilpivirine and the fixed combination containing rilpivirine, emtricitabine, and tenofovir (Complera) have not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Experience in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic and/or renal function and potential for concomitant disease and drug therapy.
For more Drug Warnings (Complete) data for Rilpivirine (13 total), please visit the HSDB record page.

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Pharmacodynamics
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor that inhibits the replication of HIV-1. It has a long duration of action as the oral tablet is given daily and the intramuscular suspension is given monthly. Patients should be counselled regarding the risk of hypersensitivity reactions, hepatotoxicity, depressive disorders, and the redistribution or accumulation of body fat.

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Rilpivirine (R278474; TMC278) is a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection [2]
Rilpivirine (R278474; TMC278) exerts its antiviral effect by binding to the NNRTI-binding pocket of HIV-1 reverse transcriptase, inhibiting viral DNA synthesis through allosteric modulation of the enzyme [1]
Rilpivirine (R278474; TMC278) was identified through a multidisciplinary drug discovery program involving structure-based design, synthetic chemistry, and in vitro/in vivo pharmacology [1]
Rilpivirine (R278474; TMC278) exhibits improved potency against NNRTI-resistant HIV-1 strains compared to first-generation NNRTIs (efavirenz, nevirapine) [2]
Rilpivirine (R278474; TMC278) is designed for once-daily oral administration due to its long half-life and sustained plasma concentrations [2]

C22H18N6

366.42

366.159

500287-72-9

Rilpivirine hydrochloride;700361-47-3;Rilpivirine-d6;1312424-26-2

6451164

Light yellow to yellow solid powder

1.3±0.1 g/cm3

634.1±65.0 °C at 760 mmHg

245ºC

337.3±34.3 °C

0.0±1.9 mmHg at 25°C

1.665

3.63

97.42

2

6

5

28

607

0

CC1=CC(=CC(=C1NC2=NC(=NC=C2)NC3=CC=C(C=C3)C#N)C)/C=C/C#N

YIBOMRUWOWDFLG-ONEGZZNKSA-N

InChI=1S/C22H18N6/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19/h3-9,11-13H,1-2H3,(H2,25,26,27,28)/b4-3+

4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile

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: ≥ 3 mg/mL (8.19 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 30.0 mg/mL 澄清的 DMSO 储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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: 3 mg/mL (8.19 mM) 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), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 30.0 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: ≥ 3 mg/mL (8.19 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 30.0 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。