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Etravirine

Etravirine (ETR,[3]), sold under the brand name Intelence is an antiretroviral medication used for the treatment of HIV.[1] Etravirine is a human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI).[1] Unlike agents in the class, resistance to other NNRTIs does not seem to confer resistance to etravirine.[4] Etravirine is marketed by Janssen, a subsidiary of Johnson & Johnson. In January 2008, the US Food and Drug Administration (FDA) approved its use for people with established resistance to other drugs, making it the 30th anti-HIV drug approved in the United States and the first to be approved in 2008.[5] It was also approved for use in Canada in April 2008.[6]

Etravirine is licensed in the United States, Canada, Israel, Russia, Australia, New Zealand, and the European Union,[7] and is under regulatory review in Switzerland.[8]

Medical uses

In the US, etravirine is indicated for the treatment of HIV-1 infection in treatment-experienced patients aged two years of age and older.[1]

In the EU, etravirine, in combination with a boosted protease inhibitor and other antiretrovirals, is indicated for the treatment of human-immunodeficiency-virus-type-1 (HIV-1) infection in antiretroviral-treatment-experienced people aged six years of age and older.[2]

Contraindication

People with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this etravine.[9]

Adverse effects

In 2009, the FDA prescribing information for etravirine was modified to include "postmarketing reports of cases of Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver failure."[10]

Mechanism of action

Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), designed to be active against HIV with mutations that confer resistance to the two most commonly prescribed first-generation NNRTIs, mutation K103N for efavirenz and Y181C for nevirapine.[11] This potency appears to be related to etravirine's flexibility as a molecule. Etravirine is a diarylpyrimidine (DAPY), a type of organic molecule with some conformational isomerism that can bind the enzyme reverse transcriptase in multiple conformations, allowing for a more robust interaction between etravirine and the enzyme, even in the presence of mutations.[12]

Chemistry

Etravine forms as colourless orthorhombic crystals in space group Pna21.[13] The structures of these and of a number of solvate and salt forms have been reported.[13][14]

Research

Etravine has been studied for use in a drug repositioning application. Etravirine was shown to cause an increase in frataxin production.[15]

References

  1. Intelence- etravirine tablet DailyMed, 15 August 2023, retrieved 14 August 2024^
  2. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Intelence EPAR European Medicines Agency (EMA), 28 August 2008, retrieved 14 August 2024^
  3. Appendix A: Key to Acronyms Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, Department of Health and Human Services^
  4. Antiviral drugs in the treatment of AIDS: what is in the pipeline ? European Journal of Medical Research, October 2007^
  5. FDA Approves HIV Drug Etravirine Associated Press, 18 January 2008^
  6. First New NNRTI in Nearly a Decade to Benefit Canadians with HIV/AIDS Janssen-Ortho Inc., 1 April 2008, retrieved 9 July 2008^
  7. Intelence receives marketing authorisation in the European Union for HIV combination therapy Tibotec, retrieved 29 August 2008^
  8. Etravirine (TMC125, Intelence) granted accelerated approval in US aidsmap, retrieved 24 January 2008^
  9. Etravine: Summary of product characteristics EMEA, retrieved 13 July 2011^
  10. FDA Medwatch Safety Information Food and Drug Administration, retrieved 27 August 2009^
  11. Etravirine—Countdown to Launch AIDSmeds.com, 15 January 2008, retrieved 2 February 2008^
  12. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants Journal of Medicinal Chemistry, May 2004^
  13. New Solid Forms of the Anti-HIV Drug Etravirine: Salts, Cocrystals, and Solubility Crystal Growth & Design, 7 August 2013^
  14. New solvates and a salt of the anti-HIV compound etravirine Acta Crystallographica Section C: Structural Chemistry, November 2021^
  15. Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia Movement Disorders, March 2019^