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Efavirenz
Systematic (IUPAC) name
(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1 H-3,1-benzoxazin-2-one
Identifiers
CAS number 154598-52-4
ATC code J05AG03
PubChem 64139
DrugBank APRD00059
ChemSpider 57715
Chemical data
Formula C 14H9ClF3NO2  
Mol. mass 315.675 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Protein binding 99.5-99.75%
Metabolism Hepatic (CYP3A4 and CYP2B6-mediated)
Half life 40-55 hours
Excretion Renal and fecal
Therapeutic considerations
Pregnancy cat. D (U.S.)
Legal status POM (UK), ℞-only (U.S.)
Routes Oral
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Efavirenz (brand names Sustiva and Stocrin) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1.

For HIV infection that has not previously been treated, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines currently recommends the use of efavirenz in combination with lamivudine/zidovudine (Combivir) or tenofovir/emtricitabine (Truvada) as the preferred NNRTI-based regimens in adults and adolescents.

Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex etc.).

The usual adult dose is 600 mg once a day. It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.

Efavirenz was combined with the popular HIV medication Truvada, which consists of tenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications approved by the U.S. Food and Drug Administration (FDA) in July 2006 under the brand name Atripla, provides HAART in a single tablet taken once a day. It results in a simplified drug regimen for many patients.

Contents

History

Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.

Indications

Efavirenz is used to treat HIV infection. It is never used alone and is always given in combination with other drugs. The decision on when to start treatment should take into account CD4 count, HIV viral load, treatment history, resistance profiles and patient preference.

Since the preliminary publication of the results of the ACTG 5142 trial in 2006 which compared efavirenz against lopinavir, efavirenz has been used as first line treatment in preference to the protease inhibitors. The ACTG 5095 trial showed that the potency of efavirenz is maintained at all CD4 counts and HIV viral loads.

Mode of action

Efavirenz falls in the NNRTI class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the reverse transcriptase enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs act allosterically by binding to a distinct site away from the active site known as the NNRTI pocket.

Efavirenz is not effective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure, which confers intrinsic resistance to the NNRTI class.[1]

As most NNRTIs bind within the same pocket, viral strains which are resistant to efavirenz are usually also resistant to the other NNRTIs, nevirapine and delavirdine. The most common mutation observed after efavirenz treatment is K103N, which is also observed with other NNRTIs.[2]

Dosing

The usual adult dose of efavirenz is 600 mg per day (usually given at bedtime); or 800 mg daily when given concurrently with rifampicin as part of treatment of co-infection with tuberculosis.

Drug interactions

  • Efavirenz is metabolized in the liver, and possesses both inhibitory and inducing effects on the 3A4 isoform of the cytochrome P450 system. This means efavirenz may interact with other drugs metabolized in the liver, requiring either increased or decreased dosages.
  • Efavirenz lowers blood levels of most protease inhibitors. Dosages of amprenavir, atazanavir, or indinavir may need to be increased. The blood levels of saquinavir are dramatically lowered, so that the two drugs cannot be used simultaneously.
  • St John's wort and garlic supplements may decrease efavirenz blood levels.

Adverse effects

Recreational use

Pricing information

As with most HIV treatments, efavirenz is quite expensive. A one month supply of 600 mg tablets cost approximately $550 in April 2008[12]. Some emerging countries have opted to purchase Indian generics[13] such as Efavir by Cipla Ltd[14] for a fraction of the cost.

Chemical properties

Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14H9ClF3NO2. Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68 g/mol. It is practically insoluble in water (<10 µg/mL).

References

  1. ^ Ren J, Bird LE, Chamberlain PP, et al. (2002). "Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors". Proc Natl Acad Sci USA 99: 14410–15. doi:10.1073/pnas.222366699. PMID 12386343.  
  2. ^ Sustiva (efavirenz) capsules and tablets. Product information (April 2005)
  3. ^ Cespedes MS, Aberg JA. Neuropsychiatric complications of antiretroviral therapy. Drug Safety. 2006;29(10):865-74. PMID 16970510
  4. ^ Hasse B, Günthard HF, Bleiber G, Krause M. Efavirenz intoxication due to slow hepatic metabolism. Clinical Infectious Diseases. 2005 Feb 1;40(3):e22-3. PMID 15668854
  5. ^ Lowenhaupt EA, Matson K, Qureishi B, Saitoh A, Pugatch D. Psychosis in a 12-year-old HIV-positive girl with an increased serum concentration of efavirenz. Clinical Infectious Diseases. 2007 Nov 15;45(10):e128-30. PMID 17968817
  6. ^ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). (Available for download from AIDSInfo)
  7. ^ Rossi S, Yaksh T, Bentley H, van den Brande G, Grant I, Ellis R. Characterization of interference with 6 commercial delta9-tetrahydrocannabinol immunoassays by efavirenz (glucuronide) in urine. Clinical Chemistry. 2006 May;52(5):896-7. PMID 16638958
  8. ^ Röder CS, Heinrich T, Gehrig AK, Mikus G. Misleading results of screening for illicit drugs during efavirenz treatment. AIDS. 2007 Jun 19;21(10):1390-1. PMID 17545727
  9. ^ IOL: Thugs get high on stolen Aids drugs
  10. ^ Getting high on HIV drugs in S Africa. BBC News, 8 December 2008.
  11. ^ 'No Turning Back': Teens Abuse HIV Drugs. ABC News, April 6, 2009.
  12. ^ Price listed on http://drugstore.com website, 4/20/2008
  13. ^ IndiaDaily - A new trend in emerging nations - Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz
  14. ^ www.cipla.com

External links








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