MK-0518
Encyclopedia
Raltegravir is an antiretroviral drug
produced by Merck & Co.
, used to treat HIV
infection. It received approval by the U.S. Food and Drug Administration (FDA) in October 2007, the first of a new class of HIV drugs, the integrase inhibitors
, to receive such approval.
, an HIV enzyme
that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. The drug is metabolized away via glucuronidation
.
Raltegravir is taken orally twice daily. Doses of 200, 400, and 600 mg have been studied.
At the 2007 Conference on Retroviruses and Opportunistic Infections, researchers presented Phase III data showing that 77% of patients taking the 400 mg dose of raltegravir plus other antiretroviral drugs reached HIV viral loads below 400 copies, nearly twice as many compared with a control group.
at 24 and 48 weeks but achieved HIV-1 RNA
levels below detection at a more rapid rate. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol
, low-density lipoprotein cholesterol, or triglycerides.
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. Research into raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.
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."
Research on human cytomegalovirus (HCMV) terminase proteins demonstrated that Raltegravir may block viral replication of the herpesviruses
.
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
produced by Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
, used to treat HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection. It received approval by the U.S. Food and Drug Administration (FDA) in October 2007, the first of a new class of HIV drugs, the integrase inhibitors
Discovery and development of integrase inhibitors
The first human immunodeficiency virus case was reported in the 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....
, to receive such approval.
Mechanism
Raltegravir targets integraseIntegrase
Retroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
, an HIV enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. The drug is metabolized away via glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
.
Dosage
At the 2007 Conference on Retroviruses and Opportunistic Infections, researchers presented Phase III data showing that 77% of patients taking the 400 mg dose of raltegravir plus other antiretroviral drugs reached HIV viral loads below 400 copies, nearly twice as many compared with a control group.
Indications
Raltegravir was initially approved only for use in individuals whose infection has proven resistant to other HAART drugs. However, in July 2009, the FDA granted expanded approval for Raltegravir for use in all patients. As with any HAART medication, raltegravir is unlikely to show durability if used as monotherapy.Efficacy
In a study of the drug as part of combination therapy, raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenzEfavirenz
Efavirenz is a non-nucleoside reverse transcriptase inhibitor and is used as part of highly active antiretroviral therapy for the treatment of a human immunodeficiency virus type 1....
at 24 and 48 weeks but achieved HIV-1 RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
levels below detection at a more rapid rate. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, low-density lipoprotein cholesterol, or triglycerides.
Research
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 InhibitorsReverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
or Protease Inhibitors
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
. 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. Research into raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.
Research results were published in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
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."
Research on human cytomegalovirus (HCMV) terminase proteins demonstrated that Raltegravir may block viral replication of the herpesviruses
Herpesviridae
The Herpesviridae are a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein , referring to the latent, recurring infections typical of this group of viruses...
.
Tolerability
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.External links
- Manufacturer's website
- MK-0518 at Aidsmedscom
- http://www.aidsmap.com/en/news/D8457D0C-2A61-4436-B416-B9627821E50C.aspIntegrase Inhibitor Raltegravir (MK-0518) Doubles HIV Suppression in Treatment-Experienced Patients (aidsmapAidsmapaidsmap, also known as the NAM aidsmap, is a website which summarizes HIV and AIDS news for a layman audience.-Name:"NAM" originally stood for "national AIDS manual" and referred to a 1987 compendium of all information about HIV published for non-scientists in England...
28 February 2007)] - RMK-0518 Abstract from CROI 2007
- Interim Results From Phase II Study Of MK-0518
- World patent covering the potassium salt
- Raltegravir Pharmacokinetics