Article: Efavirenz

Efavirenz
Systematic (IUPAC) name
8-chloro-5-(2-cyclopropylethynyl)- 5-(trifluoromethyl)- 4-oxa-2-azabicyclo [4.4.0]deca- 7,9,11-trien-3-one
Identifiers
CAS number	154598-52-4
ATC code	J05AG03
PubChem	64139
DrugBank	APRD00059
Chemical data
Formula	C14H9NClF3O2
Mol. weight	315.675 g/mol
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

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, efavirenz and lamivudine in combination with zidovudine or tenofovir is the preferred NNRTI-based regimen.

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 taken on an empty stomach at bedtime.

History

Efavirenz was approved by the Food and Drug Administration (FDA) on September 21, 1998, making it the fourteenth approved antiretroviral drug.

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.^[1]

As all 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]

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 pregnant^[3]
• Safety in children has not been established
• Use of efavirenz can produce a false positive result in some urine tests for marijuana

Chemical structure & 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).

Reference

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
2. ^ Sustiva (efavirenz) capsules and tablets. Product information (April 2005)
3. ^ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo)