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Raltegravir

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Raltegravir

Raltegravir
Systematic (IUPAC) name
N-(4-Fluorobenzyl)-5-hydroxy-1-methyl-2-(2-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}-2-propanyl)-6-oxo-1,6-dihydro-4-pyrimidinecarboxamide
Clinical data
Trade names Isentress
AHFS/Drugs.com
MedlinePlus
Licence data EMA:, US FDA:
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
oral
Pharmacokinetic data
Protein binding 83%
Metabolism Hepatic (UGT1A1)
Biological half-life 9 hours
Excretion feces and urine
Identifiers
CAS Registry Number  N
ATC code J05
PubChem CID:
ChemSpider  YesY
UNII  YesY
ChEMBL  YesY
NIAID ChemDB
Chemical data
Formula C20H21FN6O5
Molecular mass 444.42 g/mol
 N   

Raltegravir (RAL, Isentress, formerly MK-0518) is an antiretroviral drug produced by Merck & Co., used to treat HIV infection.[1] It received approval by the U.S. Food and Drug Administration (FDA) on 12 October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval.[2][3]

In December 2011, it received FDA approval for pediatric use in patients ages 2–18, 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). 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. Older adolescents will use the adult formulation.[4]

Mechanism

Raltegravir targets integrase, 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.[5]

Dosage

Isentress tablets

Raltegravir is taken orally twice daily.[3] 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 patients as compared with a control group.

Indications

Raltegravir was initially approved only for use in individuals whose infection has proven resistant to other HAART drugs.[3] However, in July 2009, the FDA granted expanded approval for raltegravir for use in all patients.[6] As with any HAART medication, raltegravir is unlikely to show durability if used as monotherapy, due to the highly mutagenic nature of HIV.

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.[7][8]

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.[9] Research into raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.[10]

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." [11]

Research on human cytomegalovirus (HCMV) terminase proteins demonstrated that raltegravir may block viral replication of the herpesviruses.[12]

In January 2013, a Phase II trial was initiated to evaluate the therapeutic benefit of raltegravir in treating multiple sclerosis (MS).[13] 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.

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.[14]

References

  1. ^
  2. ^
  3. ^ a b c
  4. ^ http://www.everydayhealth.com/hiv-aids/1222/fda-okays-raltegravir-for-kids-teens-with-hiv.aspx?xid=aol_eh-hiv_6_20111219_&aolcat=HLT&icid=maing-grid7%7Cmain5%7Cdl10%7Csec3_lnk2%26pLid%3D122480
  5. ^ HIV Antiretroviral Agents in Development
  6. ^
  7. ^
  8. ^
  9. ^ Faster Viral Decay With Raltegravir
  10. ^ Clinical trial number NCT00554398 for "Impact of MK-0518 (Raltegravir) Intensification on HIV-1 Viral Latency in Patients With Previous Complete Viral Suppression" at ClinicalTrials.gov
  11. ^
  12. ^ Drug against AIDS could be effective against herpesvirus
  13. ^ Raltegravir (Isentress) Pilot Study in Relapsing Multiple Sclerosis (INSPIRE)
  14. ^

External links

  • Manufacturer's website
  • MK-0518 at Aidsmedscom
  • Integrase Inhibitor Raltegravir (MK-0518) Doubles HIV Suppression in Treatment-Experienced Patients (aidsmap 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


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