Raltegravir

drugbox
IUPAC_name = "N"-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide

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CAS_number = 871038-72-1
ATC_prefix = J05
ATC_suffix = AX08
PubChem = 11598201
C=20 | H=21 | F=1 | N=6 | O=5
molecular_weight = 444.42 g/mol| bioavailability =
protein_bound = 83%
metabolism = Hepatic (UGT1A1)
elimination_half-life = 9 hours
excretion = feces and urine
pregnancy_US = C
legal_UK = POM
legal_US = Rx-only
legal_status =
routes_of_administration = oral
licence_EU =Isentress
licence_US =Raltegravir

Raltegravir (MK-0518, brand name "Isentress") is an antiretroviral drug produced by Merck & Co, used to treat HIV infection. It received FDA approval in October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval.

Mechanism

Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Raltegravir, and other integrase inhibitors, are often termed strand transfer inhibitors. This refers to the process of DNA strand transfer from the viral genome to the host genome. The drug is metabolized away via glucuronidation. [ [http://www.thebody.com/content/art1352.html HIV Antiretroviral Agents in Development - The Body ] ]

Dosage

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.

Indications

Raltegravir is approved only for use in individuals whose infection has proven resistant to other HAART drugs. 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 efavirenz 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. [cite journal |author=Markowitz M, Nguyen BY, Gotuzzo E, "et al" |title=Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study |journal=J. Acquir. Immune Defic. Syndr. |volume=46 |issue=2 |pages=125–33 |year=2007 |pmid=17721395 |doi=10.1097/QAI.0b013e318157131c |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/QAI.0b013e318157131c] [cite journal |author=Stephenson J |title=Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus |journal=JAMA |volume=297 |issue=14 |pages=1535–6 |year=2007 |pmid=17426263 |doi=10.1001/jama.297.14.1535 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=17426263]

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 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. [ [http://www.thebody.com/content/art42654.html Faster Viral Decay With Raltegravir - The Body ] ] Research into Raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing. [ClinicalTrialsGov|NCT00554398|Impact of MK-0518 (Raltegravir) Intensification on HIV-1 Viral Latency in Patients With Previous Complete Viral Suppression]

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." [cite journal |author=Steigbigel RT, Cooper DA, Kumar PN, "et al" |title=Raltegravir with optimized background therapy for resistant HIV-1 infection |journal=N. Engl. J. Med. |volume=359 |issue=4 |pages=339–54 |year=2008 |month=Jul |pmid=18650512 |doi=10.1056/NEJMoa0708975 |url=http://content.nejm.org/cgi/content/abstract/359/4/339]

References

*cite journal |author=Savarino A |title=A historical sketch of the discovery and development of HIV-1 integrase inhibitors |journal=Expert Opin Investig Drugs |volume=15 |issue=12 |pages=1507–22 |year=2006 |month=Dec |pmid=17107277 |doi=10.1517/13543784.15.12.1507 |url=http://www.ingentaconnect.com/content/apl/eid/2006/00000015/00000012/art00004?token=00461400d664264f65263a3d4f58762f467c405847447b23442f5f31256f5b20655d3b

External links

* [http://www.isentress.com/ Manufacturer's website]
* [http://www.aidsmeds.com/drugs/MK-0518.htm MK-0518 at Aidsmedscom]
* [http://www.aidsmap.com/en/news/D8457D0C-2A61-4436-B416-B9627821E50C.asp Integrase Inhibitor Raltegravir (MK-0518) Doubles HIV Suppression in Treatment-Experienced Patients (Aidsmap 28 February 2007)]
* [http://www.retroconference.org/2007/Abstracts/30687.htm RMK-0518 Abstract from CROI 2007]
* [http://www.medicalnewstoday.com/medicalnews.php?newsid=37591 Interim Results From Phase II Study Of MK-0518]
* [http://www.wipo.int/pctdb/en/wo.jsp?wo=2006060712 World patent covering the potassium salt]