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].

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].

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

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

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

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

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Etravirine is excreted in breastmilk in concentrations exceeding the maternal plasma and appears to increase in concentration over time. Until more information becomes available, an alternate agent may be preferred. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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

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

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

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

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.)