Raltegravir

Source: Wikipedia, the free encyclopedia.
Raltegravir
2
Clinical data
Trade namesIsentress
Other namesRAL
AHFS/Drugs.comMonograph
MedlinePlusa608004
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60% (FDA)
Protein binding83%
MetabolismLiver (UGT1A1)
Elimination half-life9 hours
Excretionfeces and urine
Identifiers
  • 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
JSmol)
  • Cc1nnc(o1)C(=O)NC(C)(C)C\3=N\C(C(=O)NCc2ccc(F)cc2)=C(\O)C(=O)N/3C
  • InChI=1S/C20H21FN6O5/c1-10-25-26-17(32-10)16(30)24-20(2,3)19-23-13(14(28)18(31)27(19)4)15(29)22-9-11-5-7-12(21)8-6-11/h5-8,28H,9H2,1-4H3,(H,22,29)(H,24,30) checkY
  • Key:CZFFBEXEKNGXKS-UHFFFAOYSA-N checkY

Raltegravir, sold under the brand name Isentress, is an

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,

HIV integrase which is needed for viral replication.[6]

Raltegravir was approved for medical use in the United States in 2007.

combination with lamivudine, is also available.[6]

Medical uses

Isentress tablets

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
]

Efficacy

In a study of the drug as part of combination therapy, raltegravir exhibited potent and durable antiretroviral activity similar to that of

triglycerides.[11][12]

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.[13]

Mechanism of action

As an

chromosomes, a critical step in the HIV infection model.[medical citation needed] The drug is metabolized away via glucuronidation.[14]

Chemistry

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

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]

History

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]

Research

Raltegravir significantly alters HIV

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]

References

  1. ^ "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 1 April 2024.
  2. ^ "Isentress 400 mg Film-coated Tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 11 July 2021.
  3. ^ "Isentress- raltegravir tablet, film coated Isentress- raltegravir tablet, chewable Isentress- raltegravir granule, for suspension". DailyMed. Retrieved 11 July 2021.
  4. ^ "Isentress EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 12 July 2021.
  5. ^
    ISBN 978-0-85711-156-2
    .
  6. ^ a b c d e f g "Raltegravir Potassium". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
  7. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ^ a b "Isentress Drug Approval Package".
    U.S. Food and Drug Administration
    (FDA). February 22, 2008. Retrieved 2009-11-15.
  9. ^ "UPDATE 2-FDA OKs widened use of Merck's Isentress HIV drug". Reuters. 2009-07-10.
  10. ^ "FDA Okays Raltegravir for Kids, Teens with HIV".
  11. S2CID 6130143
    .
  12. PMID 17426263
    .
  13. S2CID 195685470
    .
  14. ^ "HIV Antiretroviral Agents in Development". www.thebody.com. 30 March 2006.
  15. ISBN 978-0-470-76859-4
    .
  16. S2CID 75449475
    .
  17. ^ WO patent 2013098854, Gurjar MK, Sonawane SP, Maikap GS, Patil GD, Shinde SB, Patil PS Mehta SS, "Synthesis of raltegravir", published 2013-07-04, assigned to Emcure Pharmaceuticals Ltd 
  18. ^ "FDA approval of Isentress (raltegravir)".
    U.S. Food and Drug Administration (FDA). June 25, 2009. Archived from the original
    on July 10, 2009. Retrieved 2009-11-15.
  19. PMID 22035460
    .
  20. PMID 18763751
    .
  21. ^ "Faster Viral Decay With Raltegravir". www.thebodypro.com. 24 July 2007.
  22. ^ 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
  23. PMID 18650512
    .
  24. ^ "Drug against AIDS could be effective against herpesvirus". ScienceDaily.
  25. ^ Giovannoni G (24 May 2017). "Raltegravir (Isentress) Pilot Study in Relapsing Multiple Sclerosis - Full Text View - ClinicalTrials.gov". clinicaltrials.gov.

External links

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