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 exhibits significant efficacy against HIV-2 (EC50=3.5 μM) and wild-type HIV-1 (50% effective concentration [EC50]=1.4 to 4.8 nM). A number of HIV-1 group M subtypes, circulating recombinant forms, and a group O virus are also inhibited by TMC125. 19 viruses had TMC125 activity with an EC50 of less than 5 nM[1].

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Etravirine (R165335; TMC125) demonstrated broad-spectrum antiviral activity against 20 NNRTI-resistant HIV-1 clinical isolates, with EC50 values ranging from 0.001 to 0.008 μM [1]
Etravirine (R165335; TMC125) showed low cytotoxicity in human PBMCs and MT-4 cells, with CC50 values > 10 μM, resulting in a selectivity index (SI) > 10000 [1]
Etravirine (R165335; TMC125) bound to the NNRTI-binding pocket of HIV-1 reverse transcriptase, inducing conformational changes that disrupt viral DNA chain elongation [1]
Etravirine (R165335; TMC125) exhibited synergistic antiviral activity when combined with NRTIs (tenofovir, lamivudine) and protease inhibitors (atazanavir) in vitro, with combination indices (CI) < 1.0 [1]
Etravirine (R165335; TMC125) was 50–100-fold more potent than first-generation NNRTIs (efavirenz, nevirapine) against multi-drug resistant HIV-1 strains [1]

The development of resistance to etravirine is very genetically resistant. TMC125 has demonstrated activity against HIV resistance to currently available NNRTIs in phase IIb trials involving treatment-experienced individuals, including those infected with virus resistant to NNRTIs and protease inhibitors (PIs), while maintaining a tolerability profile comparable to the control group[2].

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Etravirine (R165335; TMC125) reduced HIV-1 viral load by 2.8 log10 copies/mL in SCID-hu mice (implanted with human thymus/liver) after oral administration of 10 mg/kg/day for 14 days [1]
Etravirine (R165335; TMC125) exhibited dose-dependent antiviral efficacy in HIV-1-infected mice, with 95% viral load suppression at 30 mg/kg/day (oral) [1]
In treatment-experienced HIV-1 patients, Etravirine (R165335; TMC125) (400 mg twice daily) combined with other antiretrovirals reduced viral load by a mean of 1.4 log10 copies/mL at 24 weeks [2]

HIV-1 reverse transcriptase inhibition assay: Prepare a reaction mixture containing recombinant HIV-1 reverse transcriptase (wild-type or mutant), poly(rA)-oligo(dT) template-primer, and [3H]-dTTP. Incubate with serial dilutions of Etravirine (R165335; TMC125) at 37°C for 60 min. Terminate the reaction with trichloroacetic acid, filter through glass fiber filters, and measure radioactivity to calculate IC50 and Ki values [1]
Reverse transcriptase binding affinity assay: Immobilize recombinant HIV-1 reverse transcriptase on a sensor chip. Inject serial concentrations of Etravirine (R165335; TMC125) over the chip surface at 25°C. Monitor changes in refractive index via SPR to determine binding kinetics and dissociation constant (Ki) [1]

HIV-1 antiviral cell assay: Seed MT-4 cells or primary human PBMCs in 96-well plates at 2×105 cells/well. Infect with HIV-1 (wild-type or resistant strains, MOI = 0.01) and add Etravirine (R165335; TMC125) at concentrations ranging from 0.0001 to 10 μM. Incubate for 5–7 days, then measure viral p24 antigen levels by ELISA to calculate EC50 [1]
Cell cytotoxicity assay: Culture human PBMCs and MT-4 cells in 96-well plates with Etravirine (R165335; TMC125) (0.1–100 μM) for 7 days. Assess cell viability using MTT assay, and calculate CC50 and selectivity index (SI = CC50/EC50) [1]
Combination antiviral assay: Treat HIV-1-infected MT-4 cells with Etravirine (R165335; TMC125) in combination with tenofovir, lamivudine, or atazanavir at various concentration ratios. Determine EC50 values for each drug alone and in combination, then calculate combination indices (CI) using the Chou-Talalay method [1]

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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 absorption is achieved 2.5–4 hours after oral administration. Concomitant use with oral ranitidine or omeprazole to reduce gastric acid does not affect absorption. Systemic exposure (AUC) is reduced by nearly 50% when administered on an empty stomach compared to after a meal. After administration of 800 mg of radiolabeled etravirine, 93.7% is excreted in feces, of which 81.2%–86.4% is excreted unchanged. 1.2% of the dose is excreted by the kidneys and is altered. Etravirine can be removed by dialysis (hemodialysis). Distribution of etravirine in compartments other than plasma in the human body has not been evaluated. Renal clearance of etravirine is negligible (<1.2%), therefore no dose adjustment is required in patients with renal impairment. Clearance is reduced in patients with hepatitis B and/or co-infections, but the safety of etravirine does not warrant dose adjustment.

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Metabolism/Metabolites
In vitro, it is metabolized by hepatic CYP450 enzymes: CYP3A4, CYP2C9, CYP2C19. The major metabolite formed by the partial methyl hydroxylation of dimethylbenzonitrile retains less than 90% of the etravirine activity.

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Biological half-life
The half-life is 9.05–41 hours.

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The oral bioavailability of etravirine (R165335; TMC125) in humans is 42%[2].
Etravirine (R165335; TMC125) is absorbed in the human body. After oral administration of 400 mg, the peak plasma concentration (Cmax) is 1.6 μg/mL, and the time to peak concentration (Tmax) is 2.5 hours[2].
The area under the plasma concentration-time curve (AUC0-12h) of ectavirin (R165335; TMC125) in humans is 11.8 μg·h/mL when administered twice daily at 400 mg each time [2]
The volume of distribution (Vd) of ectavirin (R165335; TMC125) in humans is 110 L [2]
The plasma elimination half-life (t1/2) of ectavirin (R165335; TMC125) in humans is 41 hours [2]
Etravirin (R165335; TMC125) is mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4) and CYP2C9 [2]
Renal excretion was < 1% of the administered dose of etravirine (R165335; TMC125) [2]

Hepatotoxicity
A high incidence of elevated serum transaminases was observed in patients receiving etravirine, but only 2% to 3% of patients experienced transaminase elevations exceeding five times the upper limit of normal; this proportion may be higher in patients with concurrent hepatitis C virus infection. Most studies have shown no significant difference in the incidence of elevated liver enzymes between the etravirine treatment group and the control group. No clinically significant liver injury caused by etravirine has been reported in large clinical trials and open-access studies. Rash A rash occurs in 10% to 20% of patients receiving etravirine, typically occurring within the first 2 to 6 weeks of treatment. This incidence is higher than with other antiretroviral therapy regimens or in the control group and is a major cause of discontinuation of etravirine due to adverse events. Rash occurring during etravirine treatment may be accompanied by other symptoms of hypersensitivity reactions, including Stevens-Johnson syndrome and immune-mediated hepatitis. Clinically significant hepatotoxicity is rare, but the sponsor has received reports of hepatitis cases with rash and symptoms of hypersensitivity reactions, some of which resulted in death. The clinical characteristics of these cases have not been described in detail. Most cases of hypersensitivity hepatitis caused by non-nucleoside reverse transcriptase inhibitors occur within the first 6 weeks of treatment and are accompanied by immune hypersensitivity manifestations such as rash, fever, lymphadenopathy, and eosinophilia. Recovery is usually rapid after discontinuation of the drug, but progressive and potentially fatal liver damage can also occur.
Probability Score: D (likely to cause clinically significant liver damage).

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Effects during Pregnancy and Lactation>
◉ Overview of Drug Use During Lactation
Etravirine is excreted into breast milk at concentrations higher than maternal plasma concentrations, and these concentrations appear to increase over time. It is recommended to prioritize alternative medications until more information is available. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of breast milk transmission to below 1%, but not zero. For HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load, breastfeeding should be supported if they choose to do so. If viral load is not suppressed, pasteurized donor breast milk or formula is recommended.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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Protein binding
The plasma protein binding rate in vitro is approximately 99.9%. In vitro experiments showed that 99.6% bound to albumin and 97.66%–99.02% bound to 1-α glycoprotein.

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Etravirine (R165335; TMC125) has a plasma protein binding rate of 99.9% in human plasma [2]
In treated HIV-1 patients, the most common adverse reactions to Etravirine (R165335; TMC125) (400 mg twice daily) were rash (17%), nausea (10%), and diarrhea (8%); Grade 3-4 adverse events occurred in <5%[2]
Etravirine (R165335; TMC125) did not show significant hepatotoxicity or nephrotoxicity in clinical trials, and serum ALT, AST or creatinine levels did not show sustained changes[2]
Etravirine (R165335; TMC125) can inhibit CYP3A4 and CYP2C9 in vitro, suggesting that it may interact with the 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 showed that no QT interval prolongation was observed on electrocardiogram 8 days after administration.

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Etravirine (R165335; TMC125) is a new generation of non-nucleoside reverse transcriptase inhibitor (NNRTI) 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 and inhibiting viral DNA synthesis through allosteric regulation[1]
Etravirine (R165335; TMC125) is indicated for the treatment of HIV-1 infected adults who have previously received treatment and have viral replication and resistance to other NNRTIs[2]
The DUET-2 clinical trial showed that etravirine (R165335; TMC125) significantly improved viral load suppression and immune function recovery (increased CD4+ T cell count) in previously treated 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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.74 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)