Efavirenz

Efavirenz

Systematic (IUPAC) name
(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
Clinical data
Trade names	Sustiva, Stocrin, others
AHFS/Drugs.com	monograph
MedlinePlus	a699004
Pregnancy category	US: D (Evidence of risk)
Legal status	UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	40–45% (under fasting conditions)
Protein binding	99.5–99.75%
Metabolism	Hepatic (CYP2A6 and CYP2B6-mediated)
Onset of action	3–5 hours
Biological half-life	40–55 hours
Excretion	Urine (14–34%) and feces (16–61%)
Identifiers
CAS Number	154598-52-4 Y
ATC code	J05AG03 (WHO)
PubChem	CID: 64139
DrugBank	DB00625 Y
ChemSpider	57715 Y
UNII	JE6H2O27P8 Y
KEGG	D00896 Y
ChEBI	CHEBI:119486 Y
ChEMBL	CHEMBL223228 Y
NIAID ChemDB	032934
PDB ligand ID	EFZ (PDBe, RCSB PDB)
Chemical data
Formula	C14H9ClF3NO2
Molecular mass	315.675 g/mol
SMILES FC(F)([C@]1(OC(NC2=CC=C(C=C21)Cl)=O)C#CC3CC3)F
InChI InChI=1S/C14H9ClF3NO2/c15-9-3-4-11-10(7-9)13(14(16,17)18,21-12(20)19-11)6-5-8-1-2-8/h3-4,7-8H,1-2H2,(H,19,20)/t13-/m0/s1 Y Key:XPOQHMRABVBWPR-ZDUSSCGKSA-N Y
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Efavirenz (EFV), sold under the brand names Sustiva among others, is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It 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 tenofovir/emtricitabine (Truvada) as one of 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.).

It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.

Efavirenz was combined with the HIV medications tenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications under the brand name Atripla, provides HAART in a single tablet taken once a day.

Efavirenz was discovered at Merck Research Laboratories. It is on the WHO Model List of Essential Medicines, the most important medication needed in a basic health system.

Medical uses

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.

Adverse effects

• Psychiatric symptoms, including insomnia, nightmares, confusion, memory loss, depression, and anxiety, are common. Post-marketing report suggest the potential for inducing more severe psychiatric events such as psychosis and aggression.
• Rash, nausea, dizziness and headache may occur
• A general guideline about efavirenz and pregnancy states that efavirenz can cause birth defects and should not be used in women who might become pregnant. A later study, however, found no increased risk of overall birth defects among women exposed to efavirenz during the first trimester of pregnancy compared with exposure to other antiretroviral drugs.
• Safety in children has not been established
• Use of efavirenz can produce a false positive result in some urine tests for marijuana

Drug interactions

• Efavirenz is metabolized in the liver, and is both a substrate and inducer of the 2B6 and 3A4 isoforms 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 viruses to evolve. This condition can be potentially fatal.
• St John's wort and garlic supplements may decrease efavirenz blood levels.

Mechanism of action

Anti-HIV effects

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.

Neuropsychiatric effects

Recently, efavirenz has been found to act as a(n) 5-HT_2A receptor partial agonist (K_i = 2.2 μM), 5-HT_2C receptor ligand, serotonin and dopamine reuptake inhibitor (50% and 75% inhibition at 10 μM, respectively), vesicular monoamine transporter 2 (VMAT2) inhibitor (60% inhibition at 10 μM), and positive allosteric modulator of the GABA_A receptor. It is thought that these properties, especially its actions at the 5-HT₂ receptors, are involved in its neuropsychiatric adverse effects (e.g., depression, anxiety, hallucinations, aggression, suicidal ideation, and sleep disturbance), as they are alleviated by cyproheptadine, a drug with 5-HT₂ receptor antagonist actions.

Despite its actions at the GABA_A receptor and the SERT, DAT, and VMAT2, efavirenz fails to produce self-administration or conditioned place preference in animals, suggesting that it lacks positive reinforcing effects. However, efavirenz does show LSD-like effects in animals, including producing the head-twitch response and positive drug discrimination responding for LSD in rodents, and there is evidence that efavirenz produces LSD-like hallucinogenic effects in humans at sufficiently high doses.

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).

History

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

Society and culture

Pricing information

A one-month supply of 600 mg tablets cost approximately $550 in April 2008. Merck provides efavirenz in certain developing countries at cost, currently about $0.65 per day. Some emerging countries have opted to purchase Indian generics such as Efavir by Cipla Ltd. In Thailand, one month supply of efavirenz + truvada, as of June 2012, costs THB 2900 ($90), there's also a social program for poorer patients who can't afford even this price. In South Africa, a license has been granted to generics giant Aspen Pharmacare to manufacture, and distribute to Sub-Saharan Africa, a cost-effective antiretroviral drug.

Brand names

• Sustiva (USA, Bristol-Myers Squibb)
• Stocrin (EU, MSD)
• Aspen Efavirenz (Sub-Saharan Africa, Aspen Pharmacare)

Generic brands India:

• E.F (McNeil & Argus)
• Efavir (Cipla)
• Efcure (Emcure Pharmaceuticals)
• Efferven (Ranbaxy Laboratories)
• Estiva (Hetero)
• Evirenz (Alkem Laboratories)
• Regast (Pharmasyntez)
• Viranz (Aurobindo Pharma)

Recreational use

Abuse of efavirenz by crushing and smoking the tablets for supposed hallucinogenic and dissociative effects has been reported in South Africa, where it is used in a mixture known as whoonga and nyaope. This is believed to be because of activity at a side target, the 5-HT_2A receptor, which is better known as the target of drugs such as LSD.

References

• Sütterlin, S., Vögele, C., & Gauggel, S. (2010). Neuropsychiatric complications of Efavirenz therapy: suggestions for a new research paradigm. The Journal of Neuropsychiatry and Clinical Neurosciences, 22(4), 361-369.

External links

• Manufacturer's site
• Prescribing information