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)
Routes of administration	By mouth (capsules, tablets)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
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
Molar mass	315.675 g/mol
3D model (Jmol)	Interactive image
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. Efavirenz is used in combination with tenofovir/emtricitabine (Truvada) as well as other antiretroviral medications.

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, both 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. As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.

Medical uses

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

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.).

As of 2010 it appeared that efavirenz was safe to use during the first trimester of pregnancy.

Contraindications

People who have taken this medication before and experienced an allergic reaction should avoid taking further efavirenz dosages. Hypersensitivity reactions include Steven-Johnson syndrome, toxic skin eruptions, and erythema multiforme.

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.
• Use of efavirenz can produce a false positive result in some urine tests for marijuana
• An evaluation of the patient’s risk of Torsades de Pointes should be done since OTc prolongation can occur.
• Convulsions should be taking into concern in adult and pediatric populations who have a history of seizures.

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.

Drug Interactions

Efavirenz is broken down in the liver by enzymes that belong to the cytochrome P450 system, which include both CYP2B6 and CYP3A4. Efavirenz is a substrate of these enzymes and can decrease the metabolism of other drugs that require the same enzymes. However, efavirenz also induces these enzymes, which means the enzyme activity is enhanced and the metabolism of other drugs broken down by CYP2B6 and CYP3A4 can be increased. People who are taking both efavirenz and other drugs metabolized by the same enzymes might need the dose of their drugs to be increased or decreased.

One group of drugs that efavirenz effects are protease inhibitors, which are used for HIV/AIDS. Efavirenz will lower the blood levels of most protease inhibitors, including aprenavir, atazanavir, and indinavir. At lowered levels, protease inhibitors may not be effective in people taking both drugs, which means the virus that causes HIV/AIDS won’t be stopped from replicating and may become resistant to the protease inhibitor.

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.

On February 17, 2016, the FDA approved the generic tablet formulation to be produced by Mylan.

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. 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.

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.

Brands

As of 2016, efavirenz was marketed in various jurisdictions under the brand names Adiva, Avifanz, Efamat, Efatec, Efavir, Efavirenz , Efcure, Eferven, Efrin, Erige, Estiva, Evirenz, Filginase, Stocrin, Sulfina V, Sustiva, Virorrever, and Zuletel.

As of 2016, the combination of efavirenz, tenofovir, and emtricitabine was marketed in various jurisdictions under the brand names Atripla, Atroiza, Citenvir, Oditec, Teevir, Trustiva, Viraday, and Vonavir.

As of 2016, the combination of efavirenz, tenofovir, and lamivudine was marketed under the brand name Eflaten.