Raltegravir
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| 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 |
monograph |
| MedlinePlus |
a608004 |
| Licence data |
EMA:Link, US FDA:link |
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Pregnancy
category
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- US: C (Risk not ruled out)
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|
Legal status
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- UK: Prescription-only (POM)
- US: ℞-only
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Routes of
administration
|
oral |
| Pharmacokinetic data |
| Protein binding |
83% |
| Metabolism |
Hepatic (UGT1A1) |
| Half-life |
9 hours |
| Excretion |
feces and urine |
| Identifiers |
|
CAS Registry Number
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871038-72-1 N |
|
ATC code
|
J05AX08 |
| PubChem |
CID: 11598201 |
| ChemSpider |
16445111 Y |
| UNII |
22VKV8053U Y |
| ChEMBL |
CHEMBL254316 Y |
| NIAID ChemDB |
471309 |
| Chemical data |
| Formula |
C20H21FN6O5 |
|
Molecular mass
|
444.42 g/mol |
SMILES
- Cc1nnc(o1)C(=O)NC(C)(C)C\3=N\C(C(=O)NCc2ccc(F)cc2)=C(\O)C(=O)N/3C
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InChI
-
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) Y
Key:CZFFBEXEKNGXKS-UHFFFAOYSA-N Y
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| N (what is this?) (verify) |
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]
Contents
- 1 Mechanism
- 2 Dosage
- 3 Indications
- 4 Efficacy
- 5 Research
- 6 Tolerability
- 7 References
- 8 External links
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
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
- ^ 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. doi:10.1517/13543784.15.12.1507. PMID 17107277.
- ^ "FDA approval of Isentress (raltegravir)". U.S. Food and Drug Administration (FDA). June 25, 2009. Retrieved 2009-11-15.
- ^ a b c "Isentress Drug Approval Package". U.S. Food and Drug Administration (FDA). February 22, 2008. Retrieved 2009-11-15.
- ^ 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
- ^ HIV Antiretroviral Agents in Development
- ^ "UPDATE 2-FDA OKs widened use of Merck's Isentress HIV drug". Reuters. 2009-07-10.
- ^ 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. doi:10.1097/QAI.0b013e318157131c. PMID 17721395.
- ^ Stephenson J (2007). "Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus". JAMA 297 (14): 1535–6. doi:10.1001/jama.297.14.1535. PMID 17426263.
- ^ Faster Viral Decay With Raltegravir
- ^ 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
- ^ 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. doi:10.1056/NEJMoa0708975. PMID 18650512.
- ^ Drug against AIDS could be effective against herpesvirus
- ^ Raltegravir (Isentress) Pilot Study in Relapsing Multiple Sclerosis (INSPIRE)
- ^ Croxtall JD, Keam SJ. (2009). "Raltegravir". Drugs 69 (8): 1059–75. doi:10.2165/00003495-200969080-00007. PMID 19496631.
External links
- Manufacturer's website
- MK-0518 at Aidsmedscom[dead link]
- 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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Merck & Co., Inc.
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| Corporate directors: |
- Richard Clark
- Johnnetta Cole
- William Harrison
- William Kelley
- Rochelle Lazarus
- Thomas Shenk
- Anne Tatlock
- Samuel Thier
- Wendell Weeks
- Peter Wendell
|
|
| Products: |
- Alendronate
- Aprepitant
- Ertapenem
- Ezetimibe
- Ezetimibe/simvastatin
- Finasteride
- Fosaprepitant
- Indinavir
- Losartan
- Lovastatin
- Montelukast
- Raltegravir
- Rizatriptan
- Rofecoxib
- Simvastatin
- Sitagliptin
- Vorinostat
|
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| Publications: |
- The Merck Manuals
- Index
- Manual
- Veterinary
- Geriatrics
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|
|
Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
|
|
Entry/fusion inhibitors
(Discovery and development) |
- gp41 (Enfuvirtide (ENF, T-20))
- CCR5 (Maraviroc (MVC)
- Vicriviroc†, Cenicriviroc†, PRO 140†)
- CD4 (Ibalizumab†)
- gp120 (Fostemsavir†)
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Reverse-transcriptase
inhibitors (RTIs) |
Nucleoside and
nucleotide (NRTI) |
- Nucleoside analogues/NARTIs: Abacavir (ABC)°#
- Emtricitabine (FTC)°#
- Lamivudine (3TC)°#
- Didanosine (ddI)#
- Zidovudine (AZT, ZDV)#
- Apricitabine†
- Stampidine†
- Elvucitabine†
- Racivir†
- Amdoxovir†
- Stavudine (d4T)#
- Zalcitabine (ddC)◊
- Festinavir†
- Nucleotide analogues/NtRTIs: Tenofovir disoproxil fumarate (TDF)°#
- Tenofovir alafenamide fumarate (TAF)†
|
|
Non-nucleoside (NNRTI)
(Discovery and development) |
- (1st generation) Efavirenz (EFV)°#
- Nevirapine (NVP)#
- Delavirdine (DLV)◊
(2nd generation) diarylpyrimidines (Etravirine (ETR)- Rilpivirine (RPV)°)
- Doravirine
|
|
|
| Integrase inhibitors |
- Raltegravir (RAL)°
- Elvitegravir (EVG)°
- Dolutegravir (DTG)°
- Globoidnan A (experimental)
- MK-2048†
- BI 224436†
- Cabotegravir†
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| Maturation inhibitors |
|
|
Protease Inhibitors (PI)
(Discovery and development) |
| 1st generation |
- Fosamprenavir (FPV)
- Lopinavir (LPV)°#
- Nelfinavir (NFV)#
- Ritonavir (RTV)#
- Saquinavir (SQV)#
- Amprenavir (APV)◊
- Indinavir (IDV)◊#
- Telinavir
- Droxinavir
|
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| 2nd generation |
- Atazanavir (ATV)°
- Darunavir (DRV)°
- Tipranavir (TPV)
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|
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| Combined formulations |
- Abacavir/lamivudine°
- Abacavir/dolutegravir/lamivudine°
- Abacavir/lamivudine/zidovudine
- Atazanavir/cobicistat
- Darunavir/cobicistat
- Efavirenz/emtricitabine/tenofovir°
- Elvitegravir/cobicistat/emtricitabine/tenofovir°
- Emtricitabine/rilpivirine/tenofovir°
- Lamivudine/raltegravir
- Lamivudine/zidovudine
- Lopinavir/ritonavir°
- Tenofovir/emtricitabine°
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| Pharmacokinetic boosters |
- Ritonavir (r)
- Cobicistat (c)
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| Experimental agents |
| Uncoating inhibitors |
|
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| Transcription inhibitors |
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| Translation inhibitors |
|
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| Other |
- Abzyme
- Calanolide A
- Ceragenin
- Cyanovirin-N
- Diarylpyrimidines
- Epigallocatechin gallate (EGCG)
- Foscarnet
- Griffithsin
- Hydroxycarbamide
- Miltefosine
- Portmanteau inhibitors
- Scytovirin
- Seliciclib†
- Synergistic enhancers
- Tre recombinase
- Zinc finger protein transcription factor
- KP-1461†
- BIT225†
|
|
| Failed agents |
- Aplaviroc
- Atevirdine
- Brecanavir
- Capravirine
- Dexelvucitabine
- Emivirine
- Lersivirine
- Lodenosine
- Loviride
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
°DHHS recommended initial regimen options. ◊Formerly or rarely used agent.
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Index of viral disease
|
|
| Description |
|
|
| Disease |
- Systemic
- Cutaneous
- Zoster
- Human papillomavirus
- Zoonotic
- Symptoms and signs
|
|
| Treatment |
|
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