Etravirine

When ATH: J05AG

Pharmacological action

Antiviral (HIV) means. Non-nucleoside reverse transcriptase inhibitor of HIV-1. Directly binds to and blocks reverse transcriptase RNA- and DNA-dependent DNA polymerase activity, causing the destruction of the catalytic sites of the enzyme. Active against laboratory strains and clinical isolates of HIV-1 wild type in acutely infected T-cell lines, Human peripheral mononuclear cells and in monocytes / macrophages by human. It is active against a wide range of members of the group M HIV-1 (subtypes A, IN, FROM, D, IS, F, G) and primary isolates of G, for which it 50% effective concentration ranges from 0,7 to 21,7 nM. Exhibits pronounced antiviral activity against 56 (from 65) strains of HIV-1 with a single amino acid substitution in position RT, associated with resistance to non-nucleoside reverse transcriptase inhibitor, including the most common mutations K103N and Y181C. Amino acid substitutions, which cause a high resistance to etravirine in cell culture, mutations Y181I (13-fold change values 50% effective concentration) and Y181V (17-fold change values 50% effective concentration). Antiviral activity in cell cultures etravirine against 24 HIV-1 strains with multiple amino acid substitutions, causing resistance to nonnucleoside reverse transcriptase inhibitors and / or protease inhibitor, similar to the activity against the wild strain of HIV-1. Breeding resistant to etravirine strains of wild-type HIV-1 of different origins and different subtypes, and selection of strains of HIV-1, resistant to non-nucleoside reverse transcriptase inhibitor, It occurs at high and low viral inoculum. The development of resistance to etravirine requires a lot of reverse transcriptase mutations, of which the most frequent following: L100I, E138K, E138G, V179I, U181S and M2301. The most frequent mutation (when virological failure result when etravirine treatment) were V179F, VI791, Y181C and Y1811. Spotted limited cross-resistance between etravirine and efavirenz in 3 (from 65) mutant strains of HIV-1, carrying the mutation, which causes resistance to non-nucleoside reverse transcriptase inhibitor. Other strains of amino acid positions, associated with reduced susceptibility to etravirine and efavirenz, varied. Etravirine retains 50% an effective concentration of at least 10 nM against 83% from 6171 clinical isolates, resistant to delavirdine, efavirenz and / or nevirapine.

Pharmacokinetics

Absorption preparation (in healthy humans) It does not depend on the simultaneous ingestion of ranitidine or omeprazole, which increase gastric pH. Etravirine plasma concentrations are similar when receiving normal and fatty foods. Compared to the concentration when administered to, concentration while taking the drug before meals reduced by 17% and 51% - In the fasting state, point O. optimal absorption of the drug reached at his reception after the meal. TCMax - 4 no. Contact proteins - 99,9% (mostly to albumin - 99,6% and alpha 1-acid glycoprotein - 97,66-99,02%). Etravirine undergoes oxidative metabolism in liver microsomes under the influence of hepatic isoenzymes CYP3A and CYP2C (less) followed by glucuronidation. Reduced clearance of etravirine patients, HIV-1 and hepatitis B and / or hepatitis C., no clinical significance. End T1 / 2 - 30-40 h. Report the news - 1,2% and intestines - 93,7% (81,2-86.4% - Unchanged). Paul, age, and mild to moderate hepatic impairment did not affect the pharmacokinetics of.

Testimony

HIV-1 infection in adults, receiving antiretrovirals, including patients with resistance to non-nucleoside reverse transcriptase inhibitors (in a combination therapy).

Contraindications

Hypersensitivity, pregnancy, lactation, childhood (to 18 years). For LF containing lactose (additionally): Lactose Intolerance, lactase deficiency, malabsorption of glucose / galactose.

Dosage regimen

Inside, after meal, in combination with other. antiretroviral drugs for 200 mg 2 times a day at the same time. The maximum daily dose - 400 mg.

If you miss a dose once (not more than 6 no), you need as quickly as possible to take this dose, take the next dose at the usual time.

If more than 6 hours after administration of the drug required time, the patient should not take the missed dose, but simply resume taking the drug in the usual way.

Etravirine combination with didanosine can be used without dose adjustment. Didanosine should be taken on an empty stomach (for 1 hours before or after 2 h after administration etravirine, which is taken after meals) by 400 mg 1 once a day.

Side effect

Frequency: Often (more 1/10), often (more 1/100 less 1/10), infrequently (more 1/1000 less 1/100).

From the CCC: often - increased blood pressure; infrequently - myocardial infarction, Atrial fibrillation, angina, hemorrhagic stroke.

From the side of hematopoiesis: Parts - thrombocytopenia, anemia.

From the nervous system: often - peripheral neuropathy, headache, alarm, insomnia; rarely - seizures, collapse, amnesia, tremor, drowsiness, paraesthesia, gipesteziya, hypersomnia, confusion, disorientation, nightmares, sleep disorders, nervousness, unusual dreams.

From the senses: rarely - blurred vision, vertigo.

The respiratory system: rarely - bronchospasm, shortness of breath on exertion.

From the digestive system: often - hastroэzofahealnыy reflux, diarrhea, vomiting, nausea, abdominal pain, flatulence, gastritis; rarely - pancreatitis, hematemesis, stomatitis, constipation, dryness of the oral mucosa, vomiturition, hepatitis, fatty degeneration of the liver, cytolytic hepatitis, gepatomegaliya.

Patients, coinfected with hepatitis B and / or hepatitis C virus, there was an increase of activity ACT and ALT.

From the urinary system: often - renal failure.

For the skin: often - a rash; rare - swelling of the face, lipohypertrophy, night sweat, hyperhidrosis, prurigo, xerosis, lipodystrophy, angioedema, erythema multiforme, Stevens-Johnson syndrome.

Metabolism: often - diabetes, giperglikemiâ, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, dyslipidaemia; infrequently – anorexia.

Laboratory findings: increase in amylase, lipase, total cholesterol, LDL, TG, Glucose, GOLD, ACT, neutropenia.

Other: often - fatigue; infrequently - listlessness, immune reconstitution syndrome, hypersensitivity, gynecomastia.

The most frequent adverse events were: skin rash, diarrhea, nausea, hypertriglyceridemia.

The most common cause of drug withdrawal: skin rash (mild to moderate, generally macular, maculo-papular erythematous or), occurs in the 2nd week of treatment (rarely after the 4th week), and disappear within 1-2 weeks on continued therapy without specific treatment.

Moderately severe side effects (no more 0,5%) bыli priobretennaya lipodystrophy, angioedema, erythema multiforme and haemorrhagic stroke.

Rarely (less 0,1%) observed Stevens-Johnson syndrome.

Overdose

Treatment: artificial vomiting, gastric lavage, Activated carbon, simptomaticheskaya therapy.

Dialysis does not lead to significant removal of the drug from the high association with plasma proteins.

Drug Interactions

Etravirine is metabolized by CYP3A4 isoenzymes, CYP2C9, CYP2C19, and its metabolites undergo glucuronidation under the influence of the enzyme uridindifosfatglyukuronoziltransferazy. PM, inducing CYP3A4, CYP2C9, CYP2C19, accelerate the clearance of etravirine, thereby reducing its concentration in plasma.

The simultaneous use of etravirine with CYP3A4 inhibitors, CYP2C9, CYP2C19 slows its clearance and increases the plasma concentration.

Etravirine is a weak inducer of CYP3A4. Simultaneous with its use drugs, metabolized by CYP3A4, may reduce their concentrations in the plasma and, Consequently, reduce or shorten their therapeutic effects.

Etravirine is a weak inhibitor of the isozymes CYP2C9 and CYP2C19. Simultaneous with its use drugs, metabolized by CYP2C9 or CYP2C19, can increase their concentration in plasma and, Consequently, enhance or prolong their therapeutic effects or adverse.

Etravirine is not recommended in conjunction with others. non-nucleoside reverse transcriptase inhibitors.

While the use of tenofovir doses require no correction; Tenofovir should take 300 mg 1 once a day. Abacavir, эmtricitabin, lamivudine, stavudine, Zidovudine displayed mainly kidneys, probably, therefore etravirine, which is derived mainly intestines, does not interact with said PM.

Not recommended simultaneous use of atazanavir (400 mg 1 once a day) without simultaneous low dose ritonavir and etravirine (the concentration of atazanavir reduced by 47%, concentration of etravirine is increased by 58%).

It is not recommended to use both full dose ritonavir (600 mg 2 once a day) with etravirine, tk. possible significant decrease in plasma concentrations of etravirine, thereby reducing its therapeutic effect.

With simultaneous use of etravirine with nelfinavir nelfinavir plasma concentration increases.

Concomitant use with fosamprenavir may increase the concentration in plasma amprenavir.

Not recommended for use with other etravirine. Protease inhibitors (including as saquinavir) without simultaneous low dose ritonavir.

At the same time use a combination of tipranavir / ritonavir (500/200 mg 2 once a day) and etravirine is not recommended, tk. the concentration of tipranavir increased by 24%, and the concentration is reduced by etravirine 82%.

With simultaneous use of etravirine and a combination of fosamprenavir / ritonavir (700/100 mg 2 once a day) may require dose adjustment of these drugs.

Etravirine can be used simultaneously with combinations: atazanavir / ritonavir (300/100 mg 1 once a day), darunavir / ritonavir (600/100 mg 2 once a day), lopinavir / ritonavir (400/100 mg 2 once a day), saquinavir / ritonavir (1000/100 mg 2 once a day) without dose adjustment.

Etravirine can be used simultaneously with the combination of lopinavir / saquinavir / ritonavir (400/800-1000 / 100 mg 2 once a day) without dose adjustment.

With simultaneous use of etravirine and enfuvirtide (90 mg 2 once a day) It assumed, that they will not interact with each other.

The combination of etravirine and raltegravir (400 mg 2 once a day) It can be used without dose adjustment.

With simultaneous use of etravirine with anti-arrhythmic drugs (Amiodarone, bepridil, disopyramide, flekainid, lidokain (I /), mexiletine, propafenone, quinidine), can decrease their concentration. Care should be taken, possibly, monitor concentrations of anti-arrhythmic drug in plasma.

With simultaneous use of etravirine with warfarin concentrations of warfarin may change, therefore advisable to check the indicator of the international normalized ratio.

Etravirine should not be used concurrently with carbamazepine, fenoʙarʙitalom, phenytoin (inducers of CYP450 isoenzyme system), tk. this can cause a significant reduction in its concentration in plasma and, respectively, therapeutic effect.

Fluconazole, itraconazole, ketoconazole, posaconazole are potent inhibitors of the CYP3A4 and can increase the concentration in plasma etravirine. On the other hand, etravirine is able to reduce the concentration of ketoconazole and itraconazole plasma, since they are also substrates for CYP3A4.

Voriconazole is a CYP2C19 substrate and an inhibitor of CYP3A4 and CYP2C. The use of voriconazole in conjunction with etravirine may increase plasma concentrations of both drugs.

Azithromycin is excreted by the kidneys, and therefore, apparently, It does not interact with etravirine.

Etravirine reduces the concentration of clarithromycin (500 mg 2 once a day) in plasma 53%; However, metabolite concentration ego aktivnogo (14-hydroxy-clarithromycin) increases by 46%. 14-gidroksiklaritromitsin has reduced activity against Mycobacterium avium complex, therefore, the overall activity of clarithromycin and its metabolite against this pathogen may vary. Therefore, to treat infections, caused by Mycobacterium avium complex, it is desirable to use, etc.. PM, eg, azithromycin.

Rifampicin, rifapentine are potent inducers of CYP450 isoenzymes. Etravirine should not be used in combination with rifampicin and rifapentine, tk. This significantly reduces the concentration in plasma and etravirine, respectively, therapeutic effect.

The combination of etravirine / rifabutin (300 mg 1 once a day) It can be used without dose adjustment.

Ribavirin is excreted by the kidneys, and therefore, apparently, It does not interact with etravirine.

Application etravirine simultaneously with diazepam can increase concentration in plasma.

Dexamethasone (orally or parenterally) induces CYP3A4 isozyme and may reduce the concentration in plasma and etravirine, respectively, therapeutic effect. Dexamethasone (except for external use) should be used with caution or use alternative medicines, especially when long-term therapy.

Combination estrogen-based contraceptives (ethinylestradiol, norethisterone) and / or progesterone receptors and may be used without etravirine dose adjustments.

St. John's wort (Hypericum perforatum) It is a potent inducer of CYP450 isoenzymes. Not recommended simultaneous application LS, containing St. John's wort, with etravirine, tk. this leads to a significant reduction in its concentration in plasma and, respectively, therapeutic effect.

At the same time taking etravirine and atorvastatin (40 mg 1 once a day) last dose must be adjusted to achieve the desired clinical effect (the concentration of atorvastatin reduced by 37%, 2 concentration is increased by gidroksiatorvastatina 27%).

Pravastatin, apparently, It does not interact with etravirine.

Lovastatin, rosuvastatin and simvastatin are CYP3A4 substrates and the simultaneous use of these drugs with etravirine may reduce their concentration in plasma.

Fluvastatin, rosuvastatin and, less, pitavastatin are metabolized by CYP2C9 isoenzyme and the simultaneous application of etravirine may increase the plasma concentrations of statins. It may be necessary to adjust their doses.

Ranitidine (150 mg 2 once a day) It can be used simultaneously with etravirine without dose adjustments.

With simultaneous use of etravirine with systemic immunosuppressants (cyclosporine, sirolimus, tacrolimus) Care must be taken, etravirine may change as concentrations in plasma.

With simultaneous use of methadone (60-130 Mg per day) with etravirine and then there was no need for dose adjustment of methadone.

With simultaneous use of etravirine with sildenafil, vardenafilom, tadalafilom (50 mg) It may require adjustment of the dose to achieve the desired clinical effect (blacks with sildenafil and N-desmethyl-sildenafil were down 57% and 41% respectively).

Omeprazole (40 mg 1 once a day) It can be used simultaneously with etravirine without dose adjustments.

Paroxetine (40 mg 1 once a day) It can be used simultaneously with etravirine without dose adjustments.

Etravirine has an additive antiviral activity in combination with protease inhibitors: amprenavir, atazanavirom, darunavirom, indinavirom, lopinavir, nelfinavirom, ritonavirom, saquinavir and tipranavir; with nucleoside or nucleotide reverse transcriptase inhibitors: zalcitabine, didanozinom, stavudine, abacavir and tenofovir; a non-nucleoside reverse transcriptase inhibitors: EFV, delavirdine and nevirapine, as well as in combination with the fusion inhibitor enfuvirtide.

Etravirine provides a synergistic or additive antiviral effect in combination with nucleoside reverse transcriptase inhibitors: emtricitabine, lamivudine and zidovudine.

Cautions

Treatment should be treated by a doctor, having sufficient experience in the treatment of HIV infection.

Modern antiretroviral drugs are not a cure and does not prevent transmission of HIV to others. people with blood or sexual contact. During treatment, patients must comply with the relevant safety measures.

In the treatment of etravirine should consider history, and, possibly, the results of determining the sensitivity of HIV-1 to antiretroviral drugs. For the treatment of patients, which took place in the treatment virologic failure non-nucleoside reverse transcriptase inhibitor and the nucleoside or nucleotide reverse transcriptase inhibitors, etravirine is not recommended in combination with only nucleotide reverse transcriptase inhibitors.

Among patients, infected with both hepatitis B and / or hepatitis C virus, Treatment was discontinued due to side effects of the liver or bile ducts. Patients with chronic hepatitis B is recommended standard clinical monitoring.

Renal clearance of etravirine - less 1,2%, therefore in patients with impaired renal function, total clearance of the drug virtually unchanged, so it does not need to reduce the dose of etravirine.

Combination antiretroviral therapy is accompanied by lipodystrophy, reduction of peripheral and facial subcutaneous fat tissue, increase in the number of intra-abdominal and visceral fat, hypertrophy breast, the accumulation of fat in the area dorsotservikalnoy (the formation of fatty hump). There is evidence of the connection between visceral lipomatosis and PIs, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. Increased risk of lipodystrophy associated with the individual characteristics of the patient (advanced age, long-term antiretroviral therapy and related metabolic disorders). Clinical examination should include evaluation of visual signs of fat redistribution.

In patients with severe immunodeficiency in early (in the first weeks or months) combination antiretroviral therapy may worsen asymptomatic or residual opportunistic infections, that can lead to poor clinical status. Perhaps the development of CMV retinitis, generalized and / or focal mycobacterial infections and pneumonia, caused Pnewnocystis jiroveci. The appearance of the symptoms of inflammation requires immediate examination and, if necessary, treatment.

Not recommended therapy delavirdine, efavirenz and / or nevirapine patients, who etravirine was ineffective with virological point of view.