Etravirine

Absorption

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.

Description

Etravirine is a second-generation NNRTI. It is indicated for use in combination with other antiretroviral agents for treating HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to the currently available NNRTIs and other antiretroviral agents. The NNRTIs, along with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), are important components of the combination regimens currently used to treat HIV-1 infection. The NRTIs/NtRTIs act by competing with the natural nucleotide substrates of reverse transcriptase for incorporation into viral DNA and subsequent chain termination. By contrast, the NNRTIs bind to an allosteric site of the enzyme and disrupt the DNA polymerase function by inducing conformational changes to the catalytic site. The allosteric binding nature of NNRTIs generally results in improved safety profile since there is no known human homolog for the drug-binding site of the enzyme.
As with other NNRTIs, etravirine has many drug–drug interactions. It is a substrate of CYP3A4, CYP2C9, and CYP2C19, an inducer of 3A4, and an inhibitor of 2C9 and 2C19. Caution should be used with co-administration of inducers, inhibitors, or substrates of these enzymes. Etravirine can be synthesized starting from 5-bromo-2,4,6-trichloropyrimidine through three successive nucleophilic substitution reactions. Initial displacement with 4-aminobenzonitrile using Hu¨nig’s base, followed by reaction with sodium salt of 4-hydroxy-3,5- dimethylbenzonitrile, and subsequent ammonolysis reaction with ammonia in dioxane under pressure affords etravirine. .

The Uses of Etravirine

Etravirine is an antiretroviral (anti-HIV) drug that is part of the non nucleoside reverse transcriptase inhibitor (NNRTIs or Non Nukes) family. It is used together with other antiretrovirals in treatment-experienced adult patients, who have failed previous therapy, and have HIV-1 strains which are resistant to other retrovirals and NNRTIs. Etravirine is used to delay the progression of HIV infection. By using etravirine, your immune system should improve (increase in CD4 + count) and you will be better protected against opportunistic infections.
Etravirine does not cure AIDS or completely kill the HIV virus, but helps to prevent further damage by slowing down the production of new viruses. Treatment with etravirine does not reduce the risk of passing infection on to others. You will still be able to pass HIV by sexual contact, by blood transfer or by sharing needles. You should always use appropriate precautions to prevent passing HIV on to others.

Background

Etravirine is an antiretroviral agent more specifically classified as a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI). Etraverine is used clinically for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. On January 18, 2007, the FDA granted accelerated approved for the use of etravirine 100mg tablets in the treatment of adult HIV-1 infection documented to be resistant to therapy with other NNRTIs and antiretroviral agents. On March 26, 2012, approval was extended for use in treatment-experienced pediatric patients 6 to 18 years of age, weighing at least 16 kg. Etravarine must always be used in combination with other antiretroviral drugs.
Etravirine exerts its effects via direct inhibition of the reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1), and consequently blocks DNA-dependent and RNA-dependent polymerase activity. Etravirine does not inhibit human DNA polymerase alpha, beta or gamma.
Common side effects of use include mild to moderate rash within the first 6 weeks of therapy, nausea, diarrhea and peripheral neuropathy. Patients are advised to immediately contact their healthcare provider if a rash develops.
In 2009, postmarketing case reports of Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythema multiforme, and other hypersensitivity reactions lead to a revision of etravirine's "Warnings and Precautions," as well as notification of health care providers.
In 2013, reports of Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) in the setting of immune reconstitution, as well as more in depth information about the development of rashes in patients taking etravirine, lead to a modification of etravirine's monograph.

Indications

Etravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced patients ≥2 years of age.

What are the applications of Application

Etravirine is a novel HIV reverse transcriptase inhibitor

What are the applications of Application

Etravirine-d6 is a novel labeled HIV reverse transcriptase inhibitor

Pharmacokinetics

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

Metabolism

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.