Raltegravir

Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS.[4] It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure.[5] It is taken by mouth.[4]

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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.124.631
Chemical and physical data
FormulaC20H21FN6O5
Molar mass444.423 g·mol−1
3D model (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

Common side effects include trouble sleeping, feeling tired, nausea, high blood sugar, and headaches.[5] Severe side effects may include allergic reactions including Stevens–Johnson syndrome, muscle breakdown, and liver problems.[5] It is unclear if use during pregnancy or breastfeeding is safe.[5] Raltegravir is an HIV integrase strand transfer inhibitor which blocks the functioning of HIV integrase which is needed for viral replication.[5]

Raltegravir was approved for medical use in the United States in 2007.[5] It is on the World Health Organization's List of Essential Medicines.[6] Lamivudine/raltegravir, a combination with lamivudine, is also available.[5]

Medical uses
Isentress tablets

Raltegravir was initially approved only for use in individuals whose infection has proven resistant to other HAART drugs.[7] However, in July 2009, the U.S. Food and Drug Administration (FDA) granted expanded approval for raltegravir for use in all patients.[8] As with any HAART medication, raltegravir is unlikely to show durability if used as monotherapy, due to the highly mutagenic nature of HIV.

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). 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.[9]

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.[10][11]

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.[12]

Mechanism of action

As an integrase inhibitor, raltegravir targets integrase, enzyme common to retroviruses that integrates the viral genetic material into human chromosomes, a critical step in the HIV infection model. The drug is metabolized away via glucuronidation.[13]

Chemistry

Raltegravir has been synthesized in several ways, which have been reviewed.[14][15]

In one method used for its manufacture, 2-amino-2-methylpropanenitrile is reacted with the acid chloride of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid using N-methylmorpholine as base. The product is treated with aqueous hydroxylamine to form an 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.[16]

History

Raltegravir was the first integrase inhibitor to receive approval in the United States in October 2007.[17][7][18] It was developed by Merck and reported by Summa et al. in the Journal of Medicinal Chemistry.[19]

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.[20] Research into raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.[21]

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."[22]

Research on human cytomegalovirus (HCMV) terminase proteins demonstrated that raltegravir may block viral replication of the herpesviruses.[23]

In January 2013, a Phase II trial was initiated to evaluate the therapeutic benefit of raltegravir in treating multiple sclerosis (MS).[24] 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. "Isentress 400 mg Film-coated Tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 11 July 2021.
  2. "Isentress- raltegravir tablet, film coated Isentress- raltegravir tablet, chewable Isentress- raltegravir granule, for suspension". DailyMed. Retrieved 11 July 2021.
  3. "Isentress EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 12 July 2021.
  4. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 429. ISBN 9780857111562.
  5. "Raltegravir Potassium". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
  6. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. "Isentress Drug Approval Package". U.S. Food and Drug Administration (FDA). February 22, 2008. Retrieved 2009-11-15.
  8. "UPDATE 2-FDA OKs widened use of Merck's Isentress HIV drug". Reuters. 2009-07-10.
  9. "FDA Okays Raltegravir for Kids, Teens with HIV".
  10. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al. (October 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". Journal of Acquired Immune Deficiency Syndromes. 46 (2): 125–133. doi:10.1097/QAI.0b013e318157131c. PMID 17721395. S2CID 6130143.
  11. Stephenson J (April 2007). "Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus". JAMA. 297 (14): 1535–1536. doi:10.1001/jama.297.14.1535. PMID 17426263.
  12. Croxtall JD, Keam SJ (May 2009). "Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients". Drugs. 69 (8): 1059–1075. doi:10.2165/00003495-200969080-00007. PMID 19496631.
  13. "HIV Antiretroviral Agents in Development". www.thebody.com.
  14. Hunt JA (2010). "Raltegravir (Isentress): The First-in-Class HIV-1 Integrase Inhibitor". Modern Drug Synthesis. pp. 1–15. doi:10.1002/9780470768594.ch1. ISBN 978-0-470-76859-4.
  15. Vardanyan R, Hruby V (2016). "34: Antiviral Drugs". Synthesis of Best-Seller Drugs. pp. 719–720. doi:10.1016/B978-0-12-411492-0.00034-1. ISBN 978-0-12-411492-0. S2CID 75449475.
  16. 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
  17. "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.
  18. Durrant JD, McCammon JA (October 2011). "Molecular dynamics simulations and drug discovery". BMC Biology. 9 (1): 71. doi:10.1186/1741-7007-9-71. PMC 3203851. PMID 22035460.
  19. Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, et al. (September 2008). "Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection". Journal of Medicinal Chemistry. 51 (18): 5843–5855. doi:10.1021/jm800245z. PMID 18763751.
  20. "Faster Viral Decay With Raltegravir". www.thebodypro.com.
  21. 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
  22. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. (July 2008). "Raltegravir with optimized background therapy for resistant HIV-1 infection". The New England Journal of Medicine. 359 (4): 339–354. doi:10.1056/NEJMoa0708975. PMID 18650512.
  23. "Drug against AIDS could be effective against herpesvirus". ScienceDaily.
  24. Giovannoni G (24 May 2017). "Raltegravir (Isentress) Pilot Study in Relapsing Multiple Sclerosis - Full Text View - ClinicalTrials.gov". clinicaltrials.gov.
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