Raltegravir

Raltegravir
Clinical data
Trade names Isentress
AHFS/Drugs.com Monograph
MedlinePlus a608004
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60%(FDA)
Protein binding 83%
Metabolism Hepatic (UGT1A1)
Biological half-life 9 hours
Excretion feces and urine
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
NIAID ChemDB
ECHA InfoCard 100.124.631
Chemical and physical data
Formula C20H21FN6O5
Molar mass 444.42 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Raltegravir (RAL), sold under the brand name Isentress, is an antiretroviral drug produced by Merck & Co., used to treat HIV infection.[1]

It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[2] It received approval by the U.S. Food and Drug Administration (FDA) in 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval.[3][4] 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.[5]

Medical uses

Isentress tablets

Raltegravir was initially approved only for use in individuals whose infection has proven resistant to other HAART drugs.[4] 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. Raltegravir is taken orally twice daily.[4]

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]

Side effects

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.[9]

Mechanism of action

As an integrase inhibitor, 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.[10]

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.[11] Research into raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.[12]

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." [13]

Research on human cytomegalovirus (HCMV) terminase proteins demonstrated that raltegravir may block viral replication of the herpesviruses.[14]

In January 2013, a Phase II trial was initiated to evaluate the therapeutic benefit of raltegravir in treating multiple sclerosis (MS).[15] 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.

References

  1. ↑ Savarino A (December 2006). "A historical sketch of the discovery and development of HIV-1 integrase inhibitors". Expert Opin Investig Drugs. 15 (12): 1507–22. PMID 17107277. doi:10.1517/13543784.15.12.1507.
  2. ↑ "WHO Model List of Essential Medicines (20th List)" (PDF). World Health Organization. March 2017. Retrieved 29 June 2017.
  3. ↑ "FDA approval of Isentress (raltegravir)". U.S. Food and Drug Administration (FDA). June 25, 2009. Retrieved 2009-11-15.
  4. 1 2 3 "Isentress Drug Approval Package". U.S. Food and Drug Administration (FDA). February 22, 2008. Retrieved 2009-11-15.
  5. ↑ 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
  6. ↑ "UPDATE 2-FDA OKs widened use of Merck's Isentress HIV drug". Reuters. 2009-07-10.
  7. ↑ Markowitz M, Nguyen BY, Gotuzzo E, et al. (2007). "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". J. Acquir. Immune Defic. Syndr. 46 (2): 125–33. PMID 17721395. doi:10.1097/QAI.0b013e318157131c.
  8. ↑ Stephenson J (2007). "Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus". JAMA. 297 (14): 1535–6. PMID 17426263. doi:10.1001/jama.297.14.1535.
  9. ↑ Croxtall JD, Keam SJ (2009). "Raltegravir". Drugs. 69 (8): 1059–75. PMID 19496631. doi:10.2165/00003495-200969080-00007.
  10. ↑ HIV Antiretroviral Agents in Development
  11. ↑ Faster Viral Decay With Raltegravir
  12. ↑ 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
  13. ↑ Steigbigel RT, Cooper DA, Kumar PN, et al. (July 2008). "Raltegravir with optimized background therapy for resistant HIV-1 infection". N. Engl. J. Med. 359 (4): 339–54. PMID 18650512. doi:10.1056/NEJMoa0708975.
  14. ↑ Drug against AIDS could be effective against herpesvirus
  15. ↑ Raltegravir (Isentress) Pilot Study in Relapsing Multiple Sclerosis (INSPIRE)
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