Clinical data | |
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Trade names | Isentress |
Other names | RAL |
AHFS/Drugs.com | Monograph |
MedlinePlus | a608004 |
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Routes of administration | By mouth |
ATC code | |
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Pharmacokinetic data | |
Bioavailability | 60% (FDA) |
Protein binding | 83% |
Metabolism | Liver (UGT1A1) |
Elimination half-life | 9 hours |
Excretion | feces and urine |
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ChEBI | |
ChEMBL | |
NIAID ChemDB | |
PDB ligand | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.124.631 |
Chemical and physical data | |
Formula | C20H21FN6O5 |
Molar mass | 444.423 g·mol−1 |
3D model (JSmol) | |
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Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. [5] It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. [6] It is taken by mouth. [5]
Common side effects include trouble sleeping, feeling tired, nausea, high blood sugar, and headaches. [6] Severe side effects may include allergic reactions including Stevens–Johnson syndrome, muscle breakdown, and liver problems. [6] It is unclear if use during pregnancy or breastfeeding is safe. [6] Raltegravir is an HIV integrase strand transfer inhibitor which blocks the functioning of HIV integrase which is needed for viral replication. [6]
Raltegravir was approved for medical use in the United States in 2007. [6] It is on the World Health Organization's List of Essential Medicines. [7] Lamivudine/raltegravir, a combination with lamivudine, is also available. [6]
Raltegravir was initially approved only for use in individuals whose infection has proven resistant to other HAART drugs. [8] However, in July 2009, the U.S. Food and Drug Administration (FDA) granted expanded approval for raltegravir for use in all patients. [9] As with any HAART medication, raltegravir is unlikely to show durability if used as monotherapy, due to the highly mutagenic nature of HIV.[ medical citation needed ]
In December 2011, it approval for use in children over the age of two, taken in pill form orally twice a day by prescription with two other antiretroviral medications to form the cocktail (most anti-HIV drugs regimens for adults and children use these cocktails).[ citation needed ] Raltegravir is available in chewable form, but because the two tablet formulations are not interchangeable, the chewable pills are only approved for use in children two to 11.[ citation needed ] Older adolescents will use the adult formulation. [10] [ failed verification ]
In a study of the drug as part of combination therapy, raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate.[ medical citation needed ] After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides. [11] [12]
Raltegravir was generally well tolerated when used in combination with optimized background therapy regimens in treatment-experienced patients with HIV-1 infection in trials of up to 48 weeks' duration. [13]
As an integrase inhibitor, raltegravir targets integrase, enzyme common to retroviruses that integrates the viral genetic material into human chromosomes, a critical step in the HIV infection model.[ medical citation needed ] The drug is metabolized away via glucuronidation. [14]
Raltegravir has been synthesized in several ways, which have been reviewed. [15] [16]
In one method used for its manufacture, 2-amino-2-methylpropanenitrile is reacted with the acid chloride of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid using N-methylmorpholine as base. The product is treated with aqueous hydroxylamine to form an amidoxime. The central pyrimidone ring of the drug is then created when the amidoxime reacts with dimethyl acetylenedicarboxylate. The synthesis is completed by conversion of the remaining methyl ester of the intermediate to an amide with 4-fluorobenzylamine, followed by methylation using trimethylsulfoxonium iodide. Use of that reagent ensures the required chemoselectivity so that methylation occurs on the nitrogen atom of the pyrimidone. [17]
Raltegravir was the first integrase inhibitor to receive approval in the United States in October 2007. [18] [8] [19] It was developed by Merck and reported by Summa et al. in the Journal of Medicinal Chemistry. [20]
Raltegravir significantly alters HIV viral dynamics and decay and further research in this area is ongoing. In clinical trials patients taking raltegravir achieved viral loads less than 50 copies per millitre sooner than those taking similarly potent non-nucleoside reverse transcriptase inhibitors or protease inhibitors. This statistically significant difference in viral load reduction has caused some HIV researchers to begin questioning long held paradigms about HIV viral dynamics and decay. [21] Research into raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing. [22]
Research results were published in the New England Journal of Medicine on July 24, 2008. The authors concluded that "raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks." [23]
Research on human cytomegalovirus (HCMV) terminase proteins demonstrated that raltegravir may block viral replication of the herpesviruses. [24]
In January 2013, a Phase II trial was initiated to evaluate the therapeutic benefit of raltegravir in treating multiple sclerosis (MS). [25] The drug is active against Human Endogenous Retroviruses (HERVs) and possibly Epstein–Barr virus, which have been suggested in the pathogenesis of relapsing-remitting MS.[ citation needed ]
Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.
Didanosine, sold under the brand name Videx, is a medication used to treat HIV/AIDS. It is used in combination with other medications as part of highly active antiretroviral therapy (HAART). It is of the reverse-transcriptase inhibitor class.
Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.
Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.
Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.
Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but have been applied to other retroviruses. The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established medical use. Other classes, such as allosteric integrase inhibitors (ALLINIs) or integrase binding inhibitors (INBIs), are still experimental.
Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class.
Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz.
Dolutegravir (DTG), sold under the brand name Tivicay, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is taken by mouth.
The first human immunodeficiency virus (HIV) case was reported in the United States in the early 1980s. Many drugs have been discovered to treat the disease but mutations in the virus and resistance to the drugs make development difficult. Integrase is a viral enzyme that integrates retroviral DNA into the host cell genome. Integrase inhibitors are a new class of drugs used in the treatment of HIV. The first integrase inhibitor, raltegravir, was approved in 2007 and other drugs were in clinical trials in 2011.
Fostemsavir, sold under the brand name Rukobia, is an antiretroviral medication for adults living with HIV/AIDS who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance or safety considerations.
Abacavir/dolutegravir/lamivudine, sold under the brand name Triumeq among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It is a combination of three medications with different and complementary mechanisms of action: abacavir, dolutegravir and lamivudine.
Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide.
Doravirine/lamivudine/tenofovir, sold under the brand name Delstrigo, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains doravirine, lamivudine, and tenofovir disoproxil. It is taken by mouth.
Dolutegravir/lamivudine, sold under the brand name Dovato, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains dolutegravir, as the salt, an integrase strand transfer inhibitor (INSTI), and lamivudine, a nucleoside analogue reverse transcriptase inhibitor (NRTI). It is taken by mouth.
Daria J Hazuda is a biochemist known for discovering the first HIV Integrase Strand Transfer Inhibitors (InSTIs) and leading the development of the first HIV integrase inhibitor to gain FDA approval, Isentress (raltegravir). Her lab also determined these inhibitors' mechanism of action and ways the virus could develop resistance to them. Hazuda has also performed extensive research and led the development of antivirals for Hepatitis C Virus (HCV) including Elbasvir and Grazoprevir. She currently serves as Vice President for Infectious Diseases Discovery for Merck and Chief Scientific Officer of their MRL Cambridge Exploratory Science Center.
Cabotegravir/rilpivirine, sold under the brand name Cabenuva, is a co-packaged antiretroviral medication for the treatment of HIV/AIDS. It contains cabotegravir and rilpivirine in a package with two separate injection vials.
Charles Williams Flexner is an American physician, clinical pharmaceutical scientist, academic, author and researcher. He is a Professor of Medicine at the Johns Hopkins University School of Medicine.