Efavirenz

Efavirenz

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Systematic (IUPAC) name
(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
Clinical data
Pregnancy category	D (U.S.)
Routes of administration	Oral
Legal status
Legal status	POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Protein binding	99.5-99.75%
Metabolism	Hepatic (CYP3A4 and CYP2B6-mediated)
Biological half-life	40-55 hours
Excretion	Renal and fecal
Identifiers
CAS Number	154598-52-4
ATC code	J05AG03 (WHO)
PubChem	CID 64139
DrugBank	APRD00059
ChemSpider	57715
Chemical data
Formula	C14H9ClF3NO2
Molar mass	315.675 g/mol[[]]
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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.

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.

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.

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. This can result in incomplete inhibition of viral replication, which can allow multidrug resistant virus to evolve. This condition can potentially be fatal.
• 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, and more serious symptoms such as psychosis may occur in patients with compromised liver or kidney function.
• Rash, nausea, dizziness and headache may occur
• Efavirenz can cause birth defects and should not be used in women who might become pregnant
• Safety in children has not been established
• Use of efavirenz can produce a false positive result in some urine tests for marijuana

Recreational use

• Abuse of efavirenz by crushing and smoking the tablets for supposed hallucinogenic and dissociative effects has been reported in South Africa

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. Some emerging countries have opted to purchase Indian generics such as Efavir by Cipla Ltd 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).

External links

• Manufacturer's site
• Prescribing information