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| Clinical data | |
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| Trade names | Isentress |
| Other names | RAL |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608004 |
| License data | |
| Pregnancy category |
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| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 60% (FDA) |
| Protein binding | 83% |
| Metabolism | Liver (UGT1A1) |
| Eliminationhalf-life | 9 hours |
| Excretion | feces and urine |
| Identifiers | |
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| CAS Number | |
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| DrugBank | |
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| UNII | |
| KEGG | |
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| ChEMBL | |
| NIAID ChemDB | |
| PDB ligand | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.124.631 |
| Chemical and physical data | |
| Formula | C20H21FN6O5 |
| Molar mass | 444.423 g·mol−1 |
| 3D model (JSmol) | |
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Raltegravir, sold under the brand nameIsentress, is anantiretroviral medication used, together with othermedication, to treatHIV/AIDS.[5] It may also be used, as part ofpost exposure prophylaxis, to prevent HIV infection following potential exposure.[6] It is taken by mouth.[5]
Common side effects include trouble sleeping, feeling tired,nausea,high blood sugar, andheadaches.[6] Severe side effects may includeallergic reactions includingStevens–Johnson syndrome,muscle breakdown, andliver problems.[6] It is unclear if use duringpregnancy orbreastfeeding is safe.[6] Raltegravir is anHIV integrase strand transfer inhibitor which blocks the functioning ofHIV integrase which is needed forviral replication.[6]
Raltegravir was approved for medical use in the United States in 2007.[6] It is on theWorld Health Organization's List of Essential Medicines.[7]Lamivudine/raltegravir, acombination withlamivudine, is also available.[6]
Raltegravir was initially approved only for use in individuals whose infection has proven resistant to otherHAART 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 (mostanti-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]
In a study of the drug as part of combination therapy, raltegravir exhibited potent and durable antiretroviral activity similar to that ofefavirenz at 24 and 48 weeks but achieved HIV-1RNA levels below detection at a more rapid rate.[medical citation needed] After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of totalcholesterol,low-density lipoprotein cholesterol, ortriglycerides.[11][12]
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]
As anintegrase inhibitor, raltegravir targetsintegrase, anenzyme common to retroviruses that integrates the viral genetic material into humanchromosomes, a critical step in the HIV infection model.[medical citation needed] The drug is metabolized away viaglucuronidation.[14]
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 theacid chloride of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid usingN-methylmorpholine asbase. The product is treated with aqueoushydroxylamine to form anamidoxime. The centralpyrimidone ring of the drug is then created when the amidoxime reacts withdimethyl acetylenedicarboxylate. The synthesis is completed by conversion of the remaining methylester of the intermediate to anamide with 4-fluorobenzylamine, followed bymethylation usingtrimethylsulfoxonium iodide. Use of that reagent ensures the requiredchemoselectivity so that methylation occurs on the nitrogen atom of the pyrimidone.[17]
Raltegravir was the firstintegrase inhibitor to receive approval in the United States in October 2007.[18][8][19]It was developed byMerck and reported by Summaet al. in the Journal of Medicinal Chemistry.[20]
In July 2024, the UK'sMedicines and Healthcare products Regulatory Agency authorised the first generic raltegravir medicines for adult and paediatric patients with HIV who weigh at least 40kg. Authorisation was granted to Lupin Healthcare (UK) Limited and Zentiva Pharma UK Limited.[21]
Raltegravir significantly alters HIVviral 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 potentnon-nucleoside reverse transcriptase inhibitors orprotease 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.[22] Research into raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.[23]
Research results were published in theNew 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."[24]
Research onhuman cytomegalovirus (HCMV) terminase proteins demonstrated that raltegravir may block viral replication of theherpesviruses.[25]
In January 2013, a Phase II trial was initiated to evaluate the therapeutic benefit of raltegravir in treatingmultiple sclerosis (MS).[26] The drug is active againstHuman Endogenous Retroviruses (HERVs) and possiblyEpstein–Barr virus, which have been suggested in the pathogenesis of relapsing-remitting MS.[citation needed]
