What Are the Most Common Uses for Etravirine?

Etravirin tablets, combined with other antiretroviral drugs, are suitable for the treatment of adult patients infected with type 1 human immunodeficiency virus (HIV-1) who have undergone antiretroviral therapy. Patients are required to have evidence of viral replication and evidence of resistance to certain non-nucleoside reverse transcriptase inhibitors (NNRTI) and other antiretroviral drugs. The indication was based on analysis of results at Week 48 of two randomized, double-blind, placebo-controlled phase III clinical trials. Both trials included patients who had previously been treated and were resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI) (appeared during the screening period and / or recorded in the medical record) and patients resistant to protease inhibitors (PI). This product is added on the basis of background treatment (BR). The following aspects should be considered when using this product: the patient's treatment history and resistance tests can guide the treatment of this product. In patients with virological failure after receiving NNRTI therapy, it is not recommended to use only this product in combination with nucleoside or nucleotide reverse transcriptase inhibitors. This product is not recommended for children, adolescents and adult patients receiving first antiviral therapy. ^[1] .

Etravirin tablets, combined with other antiretroviral drugs, are suitable for the treatment of adult patients infected with type 1 human immunodeficiency virus (HIV-1) who have undergone antiretroviral therapy. Patients are required to have evidence of viral replication and evidence of resistance to certain non-nucleoside reverse transcriptase inhibitors (NNRTI) and other antiretroviral drugs. The indication was based on analysis of results at Week 48 of two randomized, double-blind, placebo-controlled phase III clinical trials. Both trials included patients who had previously been treated and were resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI) (appeared during the screening period and / or recorded in the medical record) and patients resistant to protease inhibitors (PI). This product is added on the basis of background treatment (BR). The following aspects should be considered when using this product: the patient's treatment history and resistance tests can guide the treatment of this product. In patients with virological failure after receiving NNRTI therapy, it is not recommended to use only this product in combination with nucleoside or nucleotide reverse transcriptase inhibitors. This product is not recommended for children, adolescents and adult patients receiving first antiviral therapy. ^[1] .

Drug Name

Etravirin

Hanyu Pinyin

Yi Qu Wei Lin Pian

Use classification

Reverse transcriptase inhibitor

Etravirin tablets ingredients

Main ingredients: Etravirin.
Chemical name: 4- [6-amino-5-bromo-2- (4-cyanophenamine) pyrimidin-4-oxo] -3,5-dimethylbenzonitrile.
Chemical structural formula: http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201511201512190602.png
Molecular formula: C ₂₀ H ₁₅ BrN ₆ O
Molecular weight: 435.28

Etravirin tablets

This product is white to off-white oval tablets.

Etravirin tablets indications

This product is used in combination with other antiretroviral drugs and is suitable for the treatment of adult patients infected with type 1 human immunodeficiency virus (HIV-1) who have undergone antiretroviral therapy. Patients are required to have evidence of viral replication and evidence of resistance to certain non-nucleoside reverse transcriptase inhibitors (NNRTI) and other antiretroviral drugs.
The indication was based on analysis of results at Week 48 of two randomized, double-blind, placebo-controlled phase III clinical trials. Both trials included patients who had previously been treated and were resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI) (appeared during the screening period and / or recorded in the medical record) and patients resistant to protease inhibitors (PI). This product is added on the basis of background treatment (BR).
The following aspects should be considered when using this product: the patient's treatment history and resistance tests can guide the treatment of this product. In patients with virological failure after receiving NNRTI therapy, it is not recommended to use only this product in combination with nucleoside or nucleotide reverse transcriptase inhibitors. This product is not recommended for children, adolescents and adult patients receiving first antiviral therapy.

Etravirin tablets specifications

100mg

Etravirin tablets dosage

This product must be used in combination with other antiretroviral drugs.
Adults: The recommended dose of this product is 200 mg (2 tablets), taken orally, twice a day, and taken after meals (see the [Pharmacokinetics] section). The patient should be instructed to swallow the entire tablet with a liquid such as water. Patients who cannot swallow whole tablets can disperse the tablets in a glass of water. Patients should be instructed to:
o Place tablets in 5ml (1 teaspoon) of water, or at least enough
o Stir until the water is milky
o Add more water or orange juice, milk if needed (patients should not place tablets in orange juice or milk from the beginning)
o Take immediately
o Rinse the glass several times with water, orange juice, or milk, and take all the rinsing solution each time to ensure that the patient's dose is complete.
Avoid using warm water (> 40 ° C) or carbonated drinks.
Children (less than 12 years) and adolescents (12 to 17 years): Not recommended for children and adolescents.
Elderly: This product has limited information in the elderly.
Impaired liver function: In patients with mild or moderate hepatic impairment (Child-Pugh score A or B), dose adjustment of this product is not required. The pharmacokinetics of this product have not been studied in patients with severe hepatic impairment (Child-Pugh score C). Impaired renal function: In patients with impaired renal function, dose adjustment of this product is not required.
If the patient misses this product and is within 6 hours of the regular medication time, he must take this product as soon as possible after a meal, and then receive the next treatment at the scheduled time. If the patient misses taking this product and it is more than 6 hours away from the regular medication time, then this product should not be replenished, and only need to be treated according to the established dosing schedule.

Etravirin tablets adverse reactions

Adverse Drug Reactions from Clinical Trials Based on all data from 1203 adult patients with HIV-1 infection who had previously received antiretroviral therapy in a phase III placebo-controlled clinical trial of DUET-1 and DUET-2, The safety of the product was evaluated, of which 599 patients were treated with etravirin (200 mg, twice daily) (see the [Clinical Trials] section). In these clinical trials, the median exposure time for patients in the etrevirin-treated and placebo groups were 52.3 and 51.0 weeks, respectively.
The most common adverse drug reactions (ADRs) (5%) with a degree of at least Grade 2 were rash (10.0% in the etravirin-treated group and 3.5% in the placebo-treated group), and diarrhea (7.0% in the etravirin-treated group). And placebo-treated group 11.3%), hypertriglyceridemia (6.3% in the etravirin-treated group and 4.3% in the placebo group) and nausea (5.2% in the etravirin-treated group and 4.8% in the placebo group) (See table below).
During the treatment with this product, most of the adverse drug reactions are grades 1 to 2. In the treatment group and placebo group, 22.2% and 17.2% of patients reported grade 3 or 4 adverse drug reactions, respectively. The most common grade 3 or 4 adverse drug reactions included hypertriglyceridemia (4.2% and 2.3% of the product group and placebo group), and hypercholesterolemia (the product group and placebo group were 2.2% and 2.3%), renal failure (2.0% and 1.2% in the etravirin and placebo groups), and anemia (1.7% and 1.3% in the etravirin and placebo groups, respectively).
Clinical laboratory abnormalities (Grade 3 or 4) in treatments with an incidence of 2% or more in the treatment group of this product can be seen in the table "Laboratory abnormalities in treatment". All other grade 3 and / or grade 4 adverse drug reactions occurred in less than 1.5% of patients treated with this product. In the treatment group and placebo group, 5.2% and 2.6% of patients discontinued treatment due to adverse drug reactions, respectively. The most common adverse drug reaction that caused patients to stop treatment was rash (2.2% and 0% in the treatment and placebo groups, respectively).
During the study, the rash was mostly mild to moderate, usually maculopapular to maculopapular or erythema erythematosus. Most rashes occurred during the second week of treatment and rarely occurred after the fourth week of treatment. Most rashes are self-limiting, and patients usually return to normal within 1 to 2 weeks if they continue to receive treatment (see the [Precautions] section). In the treatment group of the DUET clinical trial, female patients had a higher incidence of rash than male patients [9/60 (15.0%) of women and 51/539 (9.5%) of men reported a rash of grade 2; (5.0%) of women and 10/539 (1.9%) of men reported discontinuation due to rash] (see section [Precautions]). Compared with patients without a history of NNRTI-related rash, patients who have a history of NNRTI-related rash do not appear to have an increased risk of using this product to develop a related rash.
Table 1 summarizes the adverse drug reactions that are moderate or higher ( 2 grades) and occur in the treatment group of this product at a rate of 1%. List adverse drug reactions by system organ classification (SOC) and frequency. Laboratory abnormalities that are considered adverse drug reactions are listed in Table 2 (see Grade 3 to 4 laboratory abnormalities in treatments with an incidence of 2%).
Table 1: Etravirin-treated ADRs of 1% moderate or higher (grade 2 or higher) reported in adult patients
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201511201527560443.png
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201511201529110023.png
Among patients receiving this product, adverse drug reactions in the treatment of moderate or more moderate ( 2) incidence rates of less than 1% include:
Heart disease: angina pectoris, atrial fibrillation neurological disease: paresthesia, drowsiness, convulsions, hypoesthesia, syncope, memory loss, attention disorder,
Excessive sleep, tremor Eye disorders: blurred vision Ear and labyrinth disorders: Dizziness Respiratory, chest and mediastinal disorders: Dyspnea on exercise, bronchospasm Gastrointestinal disorders: Bloating, pancreatitis, constipation, mouth Dryness, vomiting, retching, stomatitis diseases of the skin and subcutaneous tissue: prurigo, sweating, dry skin, swelling of the face metabolic and nutritional diseases: loss of appetite, dyslipidemia systemic diseases and diseases at the site of administration: unresponsiveness Immune system diseases: drug allergy, immune rebuilding inflammatory syndrome Hepatobiliary diseases: hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis Reproductive system and breast diseases: male mammary gland development Mental diseases: sleep disorders, dreams Abnormalities, confusion, disorientation, nervousness,
Nightmare in other clinical trials, at least moderate other adverse drug reactions include acquired lipodystrophy, angioedema, polymorphic erythema, and hemorrhagic stroke. The incidence of each of these adverse reactions does not exceed 0.5 %. Reported Stevens-Johnson syndrome is rare (<0.1%) during the clinical trials of Etravirin
Toxic epidermal necrolysis is very rare (<0.01%).
The incidence of laboratory abnormalities in the treatment group 2%, clinical laboratory abnormalities (Grade 3 or 4) in the treatment of adverse drug reactions can be seen in the table below.
Table 2: Grade 3 to 4 laboratory abnormalities in treatments with an incidence of 2%
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201511201536130243.png
Lipid dystrophy In HIV-infected patients, combined antiretroviral therapy can lead to redistribution of body fat (lipid dystrophy), including loss of subcutaneous fat in the limbs and face, increased intra-abdominal and visceral fat, hyperplasia of the breast, and accumulation of fat in the neck and back ( Buffalo back).
Immune Reconstitution Inflammation Syndrome In HIV-infected patients with severe immunodeficiency at the start of antiretroviral combination therapy, they may have an inflammatory response to asymptomatic or residual opportunistic pathogens (Immune Reconstruction Inflammation Syndrome). Autoimmune diseases such as toxic diffuse goiter have also been reported in the context of immune-reconstructed inflammatory syndromes (see section [Precautions]).
Additional Information on Specific Populations In a combined analysis of DUET-1 and DUET-2 clinical trials in patients with hepatitis B and / or HCV co-infection, among patients with hepatitis B and / or HCV co-infection (n = 139), 72 Grade 3 or 4 AST levels were elevated in 9.7% and 6.0% of patients treated with this product and 67 placebo-treated patients, respectively, and Grade 3 or 4 ALT levels were found in 11.1% and 7.5% of patients, respectively. Rise. Among patients with hepatitis B and / or HCV co-infection, 1.4% of patients in the treatment group using this product and 3.0% of patients in the placebo treatment group discontinued study drug therapy due to liver or biliary system disease. Patients with chronic hepatitis must undergo standard clinical monitoring when using this product.
Adverse Drug Reactions Observed After Etravirin On The Market Immune System Diseases Reported Hypersensitivity Reactions Including Eosinophilia and Drug-Based Rash (DRESS) with Systemic Symptoms, Characterized by Rash, Primary Condition, and Rare Organ dysfunction, including liver failure (see the [Precautions] section).
Musculoskeletal and connective tissue disorders Rhabdomyolysis.

Etravirin tablets contraindications

Those who are allergic to this product or its accessories are prohibited.

Etravirin tablets precautions

Patients must be informed that current antiretroviral treatments do not cure HIV and do not prevent HIV transmission to others through blood or sexual contact. Proper precautions still need to be taken.
Severe skin and hypersensitivity warnings: Use of etravirin may cause severe or even life-threatening and fatal skin reactions; Stevens-Johnson syndrome and toxic epidermal necrolysis are rare (<0.1%). Hypersensitivity reactions, including eosinophilia and systemic symptoms of drug-induced rash (DRESS), have also been reported, characterized by rashes, primary conditions, and rare organ dysfunction, including liver failure.
If signs or symptoms of severe skin reaction or hypersensitivity (including, but not limited to, severe rash or accompanied by fever, general malaise, fatigue, muscle or joint pain, blister, oral ulcer, conjunctivitis, hepatitis, eosinophil Rash), ectravirin should be discontinued immediately. Clinical status should be monitored, including monitoring of liver function and appropriate treatment. Delayed discontinuation of etravirin after a severe rash may cause a life-threatening reaction.
Rash has been reported with etravirin. The rash is mostly mild to moderate, with most rashes appearing at 2 weeks of treatment and rarely after 4 weeks of treatment. Most rashes are self-limiting and usually return to normal within 1 to 2 weeks of continuous treatment. The incidence of rash is higher in women (see section [Adverse reactions]).
Patients with comorbidities have liver disease in patients with mild or moderate hepatic impairment (Child-Pugh A or B) and do not need to adjust the dose of this product. The pharmacokinetics of this product have not been studied in patients with severe hepatic impairment (Child-Pugh C) (see the [Dosage and Administration] and [Pharmacokinetics] sections).
Kidney disease Because of negligible renal clearance of <RTI ID = 0.0> Etravirine </ RTI> (<1.2%), no reduction in the overall body clearance of this product occurs in patients with impaired renal function. There are no special precautions or dose adjustments in patients with impaired renal function. Etravirin is highly bound to plasma proteins and therefore cannot be significantly cleared by hemodialysis or peritoneal dialysis (see [Dosage and Administration] and [Pharmacokinetics] sections).
Fat redistribution In HIV-infected patients, combined antiretroviral therapy (CART) can lead to redistribution of body fat (lipid dystrophy). The long-term effects of these events are unknown. Its mechanism of action is not fully understood. Researchers speculate that visceral adiposity is associated with protease inhibitors, while lipoatrophy is associated with nucleoside reverse transcriptase inhibitors (NRTIs). Individual factors, such as age, and drug-related factors, such as long-term antiretroviral therapy and related metabolic disorders, can increase the risk of lipodystrophy.
The clinical examination must include an assessment of the signs of fat redistribution.
Immune Reconstruction Inflammatory Syndrome In HIV-infected patients with severe immunodeficiency at the start of antiretroviral combination therapy, they may have an inflammatory response to asymptomatic or residual opportunistic pathogens and cause severe clinical disease or cause symptoms Heavier. Such reactions usually appear within the first few weeks or months after starting antiretroviral combination therapy. Related examples include cytomegalovirus retinitis, systemic and / or local mycobacterial infections, and pneumocystis pneumoniae pneumonia. If necessary, any inflammatory symptoms must be evaluated and treated. There have also been reports of autoimmune diseases such as toxic diffuse goiter during immune reconstruction; however, the timing of their occurrence is more variable and can occur months after treatment has begun (see section [Adverse reactions]).
For interaction with other drugs, see [Drug Interactions].
Keep them out of reach of children.

Etravirin tablets for pregnant and lactating women

Pregnant women investigators have not conducted appropriate and adequately controlled clinical studies of etravirin in pregnant women. In animal studies, there is no evidence of developmental toxicity or effects on reproductive function and fertility of Etravirin (see section [Pharmacological Toxicology]).
Only when the potential benefit of the patient exceeds the potential risk, can this product be treated during pregnancy.
Whether traversin is excreted by human milk during lactation is unknown. Because infants are at risk for HIV infection and adverse events, mothers receiving this product should not breastfeed.
There are no experimental data on the effects of traversin on human fertility. Etravirin treatment had no effect on mating and fertility in rats (see section [Pharmacology and Toxicology]).

Etravirin tablets for children

Children (less than 12 years) and adolescents (ages 12 to 17): This product is not recommended for children and adolescents.
There are limited data on the safety and effectiveness of this product in this patient population.

Etravirin tablets for elderly

This product has limited information in the elderly. It cannot be confirmed whether their effects differ from younger subjects. According to current clinical data, no difference in efficacy has been found between elderly and young subjects. In short, because elderly people have lower liver, kidney, or heart function, and they are more likely to have disease or other drugs, they should pay attention to the dose selection of elderly patients. In Phase III clinical trials, a total of 6 patients aged 65 years or older and 53 patients aged 56-64 years received this product. In patients older than 55 years, the types and incidence of adverse events are similar to younger patients (see [Dosage and Administration] and [Pharmacokinetics] sections).

Etravirine tablets drug interactions

Etravirin, a drug that affects the level of exposure to etravirin, is metabolized by cytochrome P450 (CYP) 3A4, CYP2C9, and CYP2C19, and then glycosylated by uridine diphosphate glucuronyltransferase (UDPGT). Drugs that induce CYP3A4, CYP2C9, or CYP2C19 can increase the clearance of etravirin, thereby reducing the plasma concentration of etravirin. If this product is used in combination with drugs that can inhibit CYP3A4, CYP2C9 or CYP2C19, it will reduce the clearance of etravirin and increase the plasma concentration of etravirin.
Etravirin Affected Drugs Etravirin is a weak inducer of CYP3A4. Combining this product with drugs mainly metabolized by CYP3A4 can cause the plasma concentration of such drugs to decrease, thereby reducing or shortening their therapeutic effect. Etravirin is a weak inhibitor of CYP2C9 and CYP2C19. Etravirin is also a weak inhibitor of P-glycoprotein, but not its substrate. Combining this product with drugs that are primarily metabolized by CYP2C9 or CYP2C19 or transported by P-glycoprotein can lead to increased plasma concentrations of such drugs, thereby increasing or prolonging their therapeutic effect or adverse events.
The known and theoretical drug interactions between Etravirin and antiretroviral and non-retroviral drugs are listed in Table 3.
Interaction table *
The interactions between etravirin and co-administered drugs are listed in Table 3 ("" indicates an increase, "" indicates a decrease, "" indicates no change, "ND" indicates not performed, and "qd" indicates Once a day, "qam" means once a day in the morning and "bid" means twice a day).
Table 3: Drug Interactions-Etravirin in combination with antiretroviral drugs
http://x1.webres.medlive.cn/drugref/AllInstructionsDrugInteraction/201511201539170286.png
http://x1.webres.medlive.cn/drugref/AllInstructionsDrugInteraction/201511201541200413.png
http://x1.webres.medlive.cn/drugref/AllInstructionsDrugInteraction/201511201602140060.png
http://x1.webres.medlive.cn/drugref/AllInstructionsDrugInteraction/201511201606130862.png
http://x1.webres.medlive.cn/drugref/AllInstructionsDrugInteraction/201511201609550301.png

Etravirin tablets overdose

There is no specific antidote for overuse of etrevirin. Etravirin overdose has limited human experience.
The treatment of overdose of etravirin includes general supportive measures, including monitoring vital signs and observing the patient's clinical condition. If relevant, active ingredients can be removed by vomiting or gastric lavage. Activated carbon can also be used to remove unabsorbed active ingredients. Due to the high binding of etravirin to plasma proteins, it is not possible for dialysis to significantly remove active ingredients.

Etravirin tablets clinical trial

The clinical efficacy of evertravirine in patients who have previously been treated comes from two ongoing randomized, double-blind, placebo-controlled phase III clinical trials, namely TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2) Analysis results of the 48-week data. These two experiments are identical in design. The following is the analysis result of the two experimental data collection.
Eligible subjects are HIV-1-infected patients with treatment experience, plasma HIV-1 RNA> 5000 copies / mL, and at least 8 weeks of stable antiretroviral drug background and the subject has passed screening or 1 or more NNRTI resistance-associated mutations through previous genotyping and 3 or more major mutations at screening
PI mutations are as follows: D30N, V32I, L33F, M46I / L, I47A / V, G48V, I50L / V, V82A / F / L / S / T, I84V, N88S, or L90M. Randomization was achieved through the purposeful use of enfuvirtide (ENF) in BR, previous use of darunavir / ritonavir (DRV / rtv), and screening for viral load. The analysis included 612 patients participating in the DUET-1 clinical trial and 591 patients participating in the DUET-2 clinical trial. These patients completed the 48-week treatment or stopped early.
At week 48 of the study, the virological response rates of patients receiving etravirin (200 mg twice daily) plus background and placebo plus background were evaluated and compared. Background treatments include darunavir / ritonavir 600/100 mg twice daily and at least 2 other antiretroviral drugs (nucleoside or nucleotide reverse transcriptase inhibitor plus Or without ganffvirtide). In the etravirin-treated and placebo-treated groups, 45.6% and 46.9% of patients were treated with enfuvirin in background antiretroviral therapy, respectively.
In the etravirin-treated group, 25.5% of patients received enfuvirtide for the first time (from scratch), compared with 26.5% in the placebo group. In the etravirin-treated and placebo-treated groups, 20.0% and 20.4% of patients, respectively, received enfuvirtide again. Virological response is defined as a confirmed undetectable viral load (<50 HIV-1 RNA copies
/ mL).
Table 4 shows the efficacy results of patients in the etravirin-treated and placebo-treated groups at Week 48 of the combined DUET-1 and DUET-2 clinical trials.
Table 4: Combined data from DUET-1 and DUET-2 clinical trials
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201511201613530822.png
Due to the significant interaction between the treatment group and enfuvirtide, it was stratified in 2 enfuvirtide (patients with or without enfuvirtide vs. patients with enfuvirtide from scratch) Perform the main analysis. The combined analysis of the 48-week clinical trials of DUET-1 and DUET-2 confirms that the etravirin group is superior to the placebo group, regardless of whether envevir is used from scratch. Proportion of patients <50 HIV-1 RNA copies / mL in patients with or without enfuvirtide was 57.0% in the etravirin group and 33.0% in the placebo group (difference 24.0%, p <0.0001) ). Among patients who started enfuvirtide from scratch, 71.2% of patients in the etravirin group achieved <50 HIV-1 RNA, compared with 58.5% of patients in the placebo group (a difference of 12.7%, p = 0.0199).
At week 48, compared with the placebo group (59 patients, 9.8%), the number of patients who reached the clinical endpoint (AIDS-defined disease or death) in the etravirin group (35 patients, 5.8%) was significantly lower. some.
Patient-reported results In the combined DUET clinical trial, at week 48 of treatment, the body health subscale of the FAHI questionnaire for patients in the etravirin-treated group achieved a statistically significant improvement from baseline levels (human immunodeficiency virus Functional evaluation of infection). The improvement was significantly greater in the etravirin-treated group than in the placebo-treated group. No statistical differences were found for the functional and overall health subscales.
Analysis of baseline genotype / phenotype and viral treatment results In DUET-1 and DUET-2 clinical trials, if there are 3 or more mutations at baseline: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F , Y181C, Y181I, Y181V, G190A, and G190S (ejtrovirin RAMs), the virological response to etravirin treatment decreased (see Table 5). These individual mutations occur in the presence of mutations related to resistance to other non-nucleoside reverse transcriptase inhibitors. V179F is always accompanied by Y181C.
Table 5: Proportion of patients with HIV-1 RNA levels less than 50 copies / mL at week 48 in the combined DUET clinical study excluding non-VF population at 48 weeks at different baseline etravirin resistance-related mutations
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201511201615270210.png
In the DUET-1 and DUET-2 clinical trials, K103N was the most common non-nucleoside reverse transcriptase inhibitor resistance-related mutation at baseline, but studies have found that it is not a mutation related to etravirine resistance. This mutation did not affect treatment response in the etravirin-treated group.
The patient's baseline ectoverine phenotype (change in sensitivity relative to a reference level) is a predictor of virological outcome.
Table 6 shows the response rates under different baseline traversin phenotypes. These baseline phenotypic groups are based on the patient population selected in the DUET-1 and DUET-2 clinical trials and do not represent the clinical sensitivity cut-off point for evetraline. In previously treated patients, these data can inform clinicians to assess the likelihood of a virological response based on pre-treatment sensitivity to etravirin.
Table 6: Response to Etravirine at Different Baseline Etravirine Phenotypes: Combined DUET Study-Excluding Nonviral Failures-"Re-Use or Non-Envevir Peptide" Patients
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201511201619220972.png

Etravirin tablets pharmacology and toxicology

Pharmacological group and pharmacological group of ATC codes: NNRTI (non-nucleoside reverse transcriptase inhibitor), ATC code: Not yet specified.
Mechanism of action Etravirin is a class of non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1 (HIV-1). Etravirin is able to directly bind reverse transcriptase (RT) and cause the enzyme's catalytic site to break, thereby blocking RNA-dependent and DNA-dependent DNA polymerase activity. Etravirin binds to reverse transcriptase through at least two different spatial conformation patterns. In a specific binding mode, the torsion flexibility of traversin can adapt to the different conformations of reverse transcriptase, while the compactness of traversin ensures that it can be significantly changed after binding to reverse transcriptase. Reset and redirect (translation and rotation). Etravirin does not inhibit human DNA polymerase alpha, beta, and gamma activities.
In vitro antiviral activity Studies on acutely infected laboratory virus strains or clinically isolated wild-type HIV-1 T cell lines, human peripheral blood mononuclear cells, and human monocytes / macrophages have found that Etravirin has a Good antiviral activity with median EC50 values ranging from 0.9 to 5.5 nM (equivalent to 0.4 to 2.4 ng / mL).
In vitro studies have demonstrated that Etravirine has antiviral activity against a range of M-group HIV-1 (subtypes A, B, C, D, E, F, G) and major group O virus strains with EC50 values of 0.7 to 21.7 nM. These EC50 values are below 50% cytotoxic concentration (15 to> 100 M).
In the presence of human serum, the EC50 value of etravirin for HIV-1 increased with a median coefficient of 5.8.
Etravirin has no antagonistic effect with any of the antiretroviral drugs studied. Etravirin and protease inhibitors ampenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tilanavir, and saquina Wei; nucleoside or nucleotide reverse transcriptase inhibitors zalcitabine, didanosine, stavudine, abacavir, and tenofovir; non-nucleoside reverse transcriptase inhibitor efavivir Len, Delavudine and Nevirapine;
When used in combination, the fusion inhibitor enfuvirtide has cumulative antiviral activity. Etravirin has cumulative and synergistic antiviral activity when used in combination with the nucleoside reverse transcriptase inhibitors emtricitabine, lamivudine, and zidovudine.
In 65 strains of HIV-1, resistance to non-nucleoside reverse transcriptase inhibitor resistance mutations caused by an amino acid substitution at the reverse transcriptase site occurred, including the most common K103N and Y181C, while ettrevirin Strong antiviral activity against 56 of them. Studies on cell lines found that the amino acid substitutions with the highest resistance to etravirin occurred in Y181I (13 times EC50 value) and Y181V (17 times EC50 value). In cell lines, Etravirin is an antivirus to HIV-1 virus strains associated with resistance to nucleoside or nucleotide reverse transcriptase inhibitors and / or protease inhibitors in 24 strains of amino acid substitutions Activity is similar to wild-type HIV-1.
In high and low virus inoculations, ectoverline-resistant virus strains were selected in vitro from wild-type HIV-1 from different sources and subtypes and HIV-1 resistant to non-nucleoside reverse enzyme inhibitors. In high virus inoculations, the production of resistant strains of wild-type HIV-1 was delayed or failed to produce resistant strains at concentrations of 40 or 200 nM ettravirin. The same results were observed in HIV-1 strains carrying single mutations K103N and Y181C that are resistant to non-nucleoside reverse transcriptase inhibitors. Irrespective of the experimental design and the original HIV-1 virus strain, resistance to etravirin usually requires multiple mutations in the reverse transcriptase site. The following mutations are most common: L100I, E138K, E138G, V179I, Y181C, and M230I.
In the Phase III clinical trials DUET-1 and DUET-2, the most common mutations in patients who failed virologically after etravirin treatment occurred at V179F, V179I, Y181C, and Y181I, which usually occur in other multiple non-nucleosides Reverse Transcriptase Inhibitor Resistance-Related Mutations (RAM) in the Context. The following mutations were most common in clinical trials of etravirin in all HIV-1 infected patients: L100I, E138G, V179F, V179I, Y181C, and H221Y.
Cross-resistance In in vitro studies, out of 65 HIV-1 mutant strains containing resistance-related mutations in non-nucleoside reverse transcriptase inhibitors, 3 mutants have limited cross-resistance to ettravirin and efavirenz medicine. In other mutant strains, the amino acid sites that lead to reduced sensitivity of traversin and efavirenz differ. Of the 6171 clinical strains resistant to deslavudine, efavirenz, and / or nevirapine, ectoverine has an EC50 value of less than 10 nM for 83% of the strains. In patients with virological failure following etravirin therapy, deslavudine, efavirenz, or nevirapine are not recommended.
Toxicology Research Preclinical safety data Investigators have conducted animal toxicology studies of ettravirin in mice, rats, rabbits, and dogs. In mice, the key target organs of etravirin are the liver and the coagulation system. Hemorrhagic cardiomyopathy is observed only in male mice, and is a secondary manifestation of vitamin K pathway-mediated severe coagulopathy. This result is considered to be irrelevant to humans. In rats, key target organs of etravirin include the liver, thyroid, and coagulation system. Etravirin exposure in mice is equal to human exposure, and in rats, it is lower than the clinical exposure at the recommended dose. In dogs, liver and gallbladder changes can occur when exposure levels are approximately 8 times the human exposure levels at the recommended dose (200 mg, twice a day).
In studies conducted in rats, mating or fertility of animals was not affected when the dose of this product was 500 mg / kg / day and the exposure level was equal to the human exposure level at the clinically recommended dose. In rats (1000 mg / kg) and rabbits (375 mg / kg), there was no teratogenicity when the exposure level of etravirin was equal to the human exposure level at the clinically recommended dose. In prenatal and postnatal developmental evaluations in rats, ettravirin at a dose of 500 mg / kg and an exposure level equal to the human exposure at the recommended clinical dose has no effect on the development of pups during lactation or post-weaning . Mice and rats were administered gavage for 104 weeks to evaluate the carcinogenicity of etrevirin. Mice were administered at daily doses of 50, 200, and 400 mg / kg and rats at doses of 70, 200, and 600 mg / kg. Etravirin is not carcinogenic in rats and male mice. Increased incidence of hepatocellular adenomas and cancers was observed in female mice. Administration of Etravirin in mice or rats did not cause a statistically significant increase in the incidence of any other benign or malignant tumors. Hepatic cytology findings in female mice were found to be endemic to rodents, related to liver enzyme induction, and have limited relevance to humans. At the highest dose tested, the systemic exposure (based on AUC) of etravirin was 0.6 times (mouse) and 0.2-0.7 times (rat) the test results at the recommended therapeutic dose (200 mg, twice a day) in humans. ).
In the in vitro Ames back mutation analysis, in vitro chromosome aberration analysis of human lymphocytes, and in vitro chromosome cleavage analysis of mouse lymphoma, the test results of ectoverine were negative regardless of the presence or absence of a metabolic activation system.
Etravirin does not induce chromosomal damage in mice's in vivo micronucleus test.

Etravirin tablets pharmacokinetics

The researchers evaluated the pharmacokinetic properties of ettravirin in healthy adult subjects and previously treated HIV-1 infected adult patients. In HIV-1 infected patients, the level of etravirin exposure was slightly lower than in healthy subjects.
There is no intravenous formulation of etravirine absorbed, therefore, the absolute bioavailability of etravirine is unknown. After taking oral etravirin after a meal, the maximum plasma concentration is usually reached within 4 hours. In healthy adult subjects, the absorption of etravirin is not affected by oral ranitidine or omeprazole, and the latter two drugs are known to increase gastric pH.
Effects of food on absorption Similar levels of exposure were found after taking etravirin after taking a standard normal calorie diet (561 kcal) or a high-fat high calorie diet (1160 kcal). Compared with taking a standard normal calorie diet after taking the standard normal calorie diet, take it before taking the standard normal calorie diet (17%), after taking a croissant (20%) or on a fasting state (51%) Exposure levels decreased after taking etravirin. Therefore, in order to achieve the optimal level of exposure, it should be taken after meals.
Distributed in vitro, the binding rate of Etravirin to plasma proteins is about 99.9%, mainly binding to albumin (99.6%) and 1-acid glycoprotein (97.66% to 99.02%). Researchers have not evaluated the distribution of etravirin in compartments other than plasma (eg, cerebrospinal fluid, gastrointestinal secretions) in humans.
Metabolism In vitro tests in human liver microsomes (HLM) show that etrevirin is mainly oxidatively metabolized by the liver cytochrome CYP450 (CYP3A) system and also by the CYP2C family, but to a lesser extent, followed by glucoside acidification.
After taking radiolabeled 14C-etrevirin, the dose recovery rates in feces and urine were 93.7% and 1.2%, respectively. In the stool, the drug prototype of etravirin accounts for 81.2% to 86.4%. No protoviral drug was detected in urine. Etravirin has a terminal clearance half-life of approximately 30 to 40 hours. Special Populations Children and Adolescents There are currently international pharmacokinetic data of ettravirin in children and adolescents (ages 6 to 18), and pharmacokinetics of ettravirin in children younger than 6 years the study.
Population pharmacokinetic analysis of older people in HIV-infected patients showed no significant differences in the pharmacokinetics of etravirin over the age range evaluated (18 to 77 years).
Gender There was no significant difference in the pharmacokinetics of etravirin between male and female patients. The number of women participating in the study is limited.
The ethokinelin pharmacokinetic analysis of humans in HIV-infected patients showed that the human race had no significant effect on the level of etravirin exposure.
Impaired liver function Etravirin is primarily metabolized and eliminated in the liver. In a study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) and 8 matched controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) and 8 matched controls, Multiple administrations of Etravirin in patients with mild to moderate hepatic impairment,
The pharmacokinetic distribution is unaffected. In patients with mild or moderate hepatic impairment, no dose adjustment is needed.
Etravirin has not been studied in patients with severe hepatic impairment (Child-Pugh score C).
Co-infection with hepatitis B and / or hepatitis C virus
Population pharmacokinetic analysis of the DUET-1 and DUET-2 clinical trials showed a decrease in etravirin clearance in patients co-infected with HIV-1 and hepatitis B and / or HCV. Based on safety data (see section [Adverse Reactions]), it is not necessary to adjust the dose of etravirin in patients co-infected with HIV-1 and HBV and / or HCV.
Renal Impairment The pharmacokinetics of ettravirin have not been studied in patients with renal insufficiency. The results of a mass balance study using the radioactive marker 14C-Etravirin showed that the dose of radioactive marker excreted in urine was <1.2%. No prototype drug was detected in urine, so impaired renal function had minimal effect on etravirin clearance. Due to the high binding of Etravirin to plasma proteins, it is impossible to be significantly cleared by hemodialysis or peritoneal dialysis (see the [Dosage and Administration] and [Caution] sections).

Etravirin tablets storage

Keep tightly closed up to 30 ° C.

Etravirin tablets packaging

High density polyethylene plastic bottle with caps that are not easy for children to open. 120 tablets / bottle / box.

Etravirin tablets expiration date

24 months.

Etravirin film implementation standards

JX20080314