Efavirenz

drugbox
IUPAC_name = (4"S")-6-chloro-4-(cyclopropylethynyl)-4- (trifluoromethyl)-1,4-dihydro-2"H"-3,1-benzoxazin-2-one

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width = 150
CAS_number = 154598-52-4
ATC_prefix = J05
ATC_suffix = AG03
PubChem = 64139
DrugBank = APRD00059
C = 14 | H = 9 | Cl = 1 | F = 3 | N = 1 | O = 2
molecular_weight = 315.675 g/mol
smiles = Clc1ccc2NC(=O)O [C@@] (C#CC3CC3)(c2c1)C(F)(F)F
bioavailability =
protein_bound = 99.5-99.75%
metabolism = Hepatic (CYP3A4 and CYP2B6-mediated)
elimination_half-life = 40-55 hours
excretion = Renal and fecal
pregnancy_category = D (U.S.)
legal_status = POM (UK), ℞-only (U.S.)
routes_of_administration = Oral

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 onAntiretroviral 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 prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission.

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 FDA in July 2006 under the brand name Atripla, provides highly active antiretroviral therapy (HAART) in a single tablet taken once a day. It results in a simplified drug regimen for many patients.

History

Efavirenz was approved by the Food and Drug Administration (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 non-nucleoside reverse transcriptase inhibitor (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 bind within a pocket termed 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. [cite journal | author=Ren J, Bird LE, Chamberlain PP, "et al." | year=2002 | title=Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors | journal=Proc Natl Acad Sci USA | volume=99 | pages=14410–15 | pmid=12386343 | doi=10.1073/pnas.222366699]

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. [ [http://www.bms.com/cgi-bin/anybin.pl?sql=select+PPI+from+TB_PRODUCT_PPI+where+PPI_SEQ=94&key=PPI Sustiva (efavirenz) capsules and tablets. Product information (April 2005)] ]

Dosing

The usual adult dose of efavirenz is 600mg per day (usually given at bedtime); or 800mg 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

*Psychiatric symptoms, including insomnia, confusion, memory loss, and depression, are common
*Rash, nausea, dizziness and headache may occur
*Efavirenz can cause birth defects and should not be used in women who might become pregnantDHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). (Available for download from [http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 AIDSInfo] )]
*Safety in children has not been established
*Use of efavirenz can produce a false positive result in some urine tests for marijuana
*Abuse of efavirenz for supposed hallucinogenic and dissociative effects has been reported in South Africa [ [http://www.iol.co.za/index.php?from=rss_South+Africa&set_id=1&click_id=13&art_id=vn20070512085358794C523744 IOL: Thugs get high on stolen Aids drugs ] ]

Pricing information

As with most HIV treatments, efavirenz is quite expensive. A one month supply of 600mg tablets cost approximately $550 in April 2008 [Price listed on http://drugstore.com website, 4/20/2008] . Some emerging countries have opted to purchase Indian generics [ [http://www.indiadaily.com/editorial/16665.asp IndiaDaily - A new trend in emerging nations - Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz ] ] such as Efavir by Cipla Ltd [www.cipla.com] for a fraction of the cost. Some online pharmacies carry the generic for about $10 per 600mg pill.

Chemical structure and state of matter

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

External links

* [http://www.sustiva.com/managehiv/sustiva/home/index.jsp?BV_UseBVCookie=Yes Manufacturer's site]
* [http://www.bms.com/cgi-bin/anybin.pl?sql=select+PPI+from+TB_PRODUCT_PPI+where+PPI_SEQ=94&key=PPI Prescribing information]