U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C20H21FN6O5
Molecular Weight 444.4171
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of RALTEGRAVIR

SMILES

Cc1nnc(C(=O)NC(C)(C)c2nc(c(c(=O)n2C)O)C(=NCc3ccc(cc3)F)O)o1

InChI

InChIKey=CZFFBEXEKNGXKS-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Molecular Formula C20H21FN6O5
Molecular Weight 444.4171
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Raltegravir (RAL, Isentress, formerly MK-0518) is an antiretroviral drug produced by Merck & Co., used to treat HIV and it is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in patients 4 weeks of age and older. Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required r viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryl transferases including DNA polymerases α, β, and γ. Coadministration with others drugs that are strong inducers of UGT1A1, such as rifampin, may result in reduced plasma concentrations of raltegravir. The most common adverse reactions of moderate to severe intensity (≥2%) are insomnia, headache, dizziness, nausea and fatigue. Severe, potentially life-threatening, and fatal skin reactions have been reported. This include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. The major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

Originator

Curator's Comment:: Merck & Co. Inc., Istituto Di Ricerche Di Biologia Molecolar # Merck & Co. Inc.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
10.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ISENTRESS

Approved Use

INDICATIONS & USAGE ISENTRESS is a human immunodeficiency virus integrase strand transfer inhibitor (HIV-1 INSTI) indicated: In combination with other antiretroviral agents for the treatment of HIV-1 infection (1). The safety and efficacy of ISENTRESS have not been established in children less than 2 years of age (1.2). ISENTRESS® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection. This indication is based on analyses of plasma HIV-1 RNA levels in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults through 96 weeks and one was conducted in treatment-naïve adults through 156 weeks. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response [see Clinical Studies (14)

Launch Date

1.19214716E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
142 nM
400 mg 2 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
RALTEGRAVIR plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
1300 ng/mL
400 mg 2 times / day steady, oral
dose: 400 mg
route of administration: oral
experiment type: steady
co-administered:
RALTEGRAVIR plasma
Homo sapiens
20163 nM
1200 mg single, oral
dose: 1200 mg
route of administration: oral
experiment type: single
co-administered:
RALTEGRAVIR plasma
Homo sapiens
population: healthy
age:
sex: M
food status: Fasted
830.204 ng/ml
400 mg 2 times / day steady, oral
dose: 400 mg
route of administration: oral
experiment type: steady
co-administered:
RALTEGRAVIR unknown
Homo sapiens
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
14.3 μM × h
400 mg 2 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
RALTEGRAVIR plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
4070 ng*h/mL
400 mg 2 times / day steady, oral
dose: 400 mg
route of administration: oral
experiment type: steady
co-administered:
RALTEGRAVIR plasma
Homo sapiens
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
9 h
400 mg 2 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
RALTEGRAVIR plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
7.5 h
1200 mg single, oral
dose: 1200 mg
route of administration: oral
experiment type: single
co-administered:
RALTEGRAVIR plasma
Homo sapiens
population: healthy
age:
sex: M
food status: Fasted
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
17%
400 mg 2 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
RALTEGRAVIR plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
800 mg single, oral
Highest studied dose
Dose: 800 mg
Route: oral
Route: single
Dose: 800 mg
Sources: Page: p.123
healthy, 29 +/- 13
n = 12
Health Status: healthy
Age Group: 29 +/- 13
Sex: M+F
Population Size: 12
Sources: Page: p.123
400 mg 2 times / day multiple, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources: Page: p.123
healthy, 29 +/- 13
n = 12
Health Status: healthy
Age Group: 29 +/- 13
Sex: M+F
Population Size: 12
Sources: Page: p.123
24000 mg single, oral
Overdose
Dose: 24000 mg
Route: oral
Route: single
Dose: 24000 mg
Sources: Page: p.1
unhealthy, 42
n = 1
Health Status: unhealthy
Condition: HIV-1 infection
Age Group: 42
Sex: M
Population Size: 1
Sources: Page: p.1
Disc. AE: Nausea, Abdominal pain...
AEs leading to
discontinuation/dose reduction:
Nausea (mild)
Abdominal pain
Sources: Page: p.1
400 mg 2 times / day multiple, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Disc. AE: Reaction skin, Stevens-Johnson syndrome...
AEs leading to
discontinuation/dose reduction:
Reaction skin (severe|grade 4|grade 5)
Stevens-Johnson syndrome (severe|grade 4|grade 5)
Hypersensitivity reaction (severe|grade 4|grade 5)
Toxic epidermal necrolysis (severe|grade 4|grade 5)
Immune reconstitution syndrome
Sources: Page: p.1
AEs

AEs

AESignificanceDosePopulation
Abdominal pain Disc. AE
24000 mg single, oral
Overdose
Dose: 24000 mg
Route: oral
Route: single
Dose: 24000 mg
Sources: Page: p.1
unhealthy, 42
n = 1
Health Status: unhealthy
Condition: HIV-1 infection
Age Group: 42
Sex: M
Population Size: 1
Sources: Page: p.1
Nausea mild
Disc. AE
24000 mg single, oral
Overdose
Dose: 24000 mg
Route: oral
Route: single
Dose: 24000 mg
Sources: Page: p.1
unhealthy, 42
n = 1
Health Status: unhealthy
Condition: HIV-1 infection
Age Group: 42
Sex: M
Population Size: 1
Sources: Page: p.1
Immune reconstitution syndrome Disc. AE
400 mg 2 times / day multiple, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Hypersensitivity reaction severe|grade 4|grade 5
Disc. AE
400 mg 2 times / day multiple, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Reaction skin severe|grade 4|grade 5
Disc. AE
400 mg 2 times / day multiple, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Stevens-Johnson syndrome severe|grade 4|grade 5
Disc. AE
400 mg 2 times / day multiple, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Toxic epidermal necrolysis severe|grade 4|grade 5
Disc. AE
400 mg 2 times / day multiple, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Raltegravir, a new HIV integrase inhibitor.
2007 Dec
Raltegravir (MK-0518): an integrase inhibitor for the treatment of HIV-1.
2007 Dec
FDA approves raltegravir tablets.
2007 Nov
Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase.
2007 Nov 12
Raltegravir susceptibility and fitness progression of HIV type-1 integrase in patients on long-term antiretroviral therapy.
2008
HIV infection in the elderly.
2008
HIV-1 drug resistance mutations: an updated framework for the second decade of HAART.
2008 Apr-Jun
Highlights of the 15th Conference on Retroviruses and Opportunistic Infections. Advances in antiretroviral therapy.
2008 Apr-May
Raltegravir: the first in a new class of integrase inhibitors for the treatment of HIV.
2008 Aug
Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
2008 Aug
Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel.
2008 Aug 6
An HPLC-PDA method for the simultaneous quantification of the HIV integrase inhibitor raltegravir, the new nonnucleoside reverse transcriptase inhibitor etravirine, and 11 other antiretroviral agents in the plasma of HIV-infected patients.
2008 Dec
Integrase and integration: biochemical activities of HIV-1 integrase.
2008 Dec 17
Novel druggable hot spots in avian influenza neuraminidase H5N1 revealed by computational solvent mapping of a reduced and representative receptor ensemble.
2008 Feb
Lack of a pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation.
2008 Feb
Tricyclic HIV integrase inhibitors: potent and orally bioavailable C5-aza analogs.
2008 Feb 15
Safe use of raltegravir and sirolimus in an HIV-infected patient with renal impairment after orthotopic liver transplantation.
2008 Feb 19
Integrase inhibitors: a new treatment option for patients with human immunodeficiency virus infection.
2008 Jan
Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection.
2008 Jan
New drugs: doripenem, raltegravir, and ixabepilone.
2008 Jan-Feb
Integrase inhibitors for the treatment of HIV infection.
2008 Jul
Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.
2008 Jul 10
Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval.
2008 Jun
Outcomes of multidrug-resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen.
2008 Jun 19
Raltegravir: an integrase inhibitor for HIV-1.
2008 Mar
Quinolone 3-carboxylic acid pharmacophore: design of second generation HIV-1 integrase inhibitors.
2008 Mar 13
Drug 9AA reactivates p21/Waf1 and Inhibits HIV-1 progeny formation.
2008 Mar 18
Complexity of interactions between voriconazole and antiretroviral agents.
2008 May
Successful rescue therapy with Raltegravir (MK-0518) and Etravirine (TMC125) in an hiv-infected patient failing all four classes of antiretroviral drugs.
2008 May
Quantification of the HIV-integrase inhibitor raltegravir (MK-0518) in human plasma by high-performance liquid chromatography with fluorescence detection.
2008 May 15
A sensitive HPLC-MS-MS method for the determination of raltegravir in human plasma.
2008 May 15
Trial will evaluate a once-daily dose of raltegravir.
2008 Nov
Raltegravir phase III study data released.
2008 Nov
Pharmacologic aspects of new antiretroviral drugs.
2008 Nov
HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro.
2008 Nov
Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection.
2008 Nov
Raltegravir for postexposure prophylaxis following occupational exposure to HIV.
2008 Nov 30
Raltegravir: the first HIV integrase inhibitor.
2008 Oct
Discovery of 3-acetyl-4-hydroxy-2-pyranone derivatives and their difluoridoborate complexes as a novel class of HIV-1 integrase inhibitors.
2008 Oct 1
Selection of the Q148R integrase inhibitor resistance mutation in a failing raltegravir containing regimen.
2008 Oct 1
Emerging resistance profiles of newly approved antiretroviral drugs.
2008 Oct-Nov
A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.
2008 Sep
An improved relaxed complex scheme for receptor flexibility in computer-aided drug design.
2008 Sep
Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection.
2008 Sep 25
Comparing two integrase inhibitors. The first head-to-head study comparing raltegravir and elvitegravir.
2008 Sep-Oct
Quantitative prediction of human clearance guiding the development of Raltegravir (MK-0518, isentress) and related HIV integrase inhibitors.
2009 Apr
Pharmacologic aspects of new antiretroviral drugs.
2009 Feb
Is dual therapy with raltegravir and protease inhibitors a feasible option in rescue strategy in HIV-1 infection?
2009 Feb 1
Effects of omeprazole on plasma levels of raltegravir.
2009 Feb 15
Implications of HIV-1 M group polymorphisms on integrase inhibitor efficacy and resistance: genetic and structural in silico analyses.
2009 Jan 13
Patents

Sample Use Guides

In Vivo Use Guide
Curator's Comment:: in Children and Adolescents: If at least 25 kg: One 400 mg film-coated tablet orally, twice daily. For patients weighing between 11 and 20 kg, either the chewable tablet or the formulation for oral suspension can be used.
400 mg film-coated tablet orally, twice daily. During coadministration with rifampin in adults, 800 mg twice daily
Route of Administration: Oral
The antiviral activity of Raltegravir was determined in a cell-based HIV-1 replication assay with HeLa-CD4-LTR-β-gal cells. The highest compound concentration tested was 50 μM.
Substance Class Chemical
Created
by admin
on Sat Jun 26 14:34:12 UTC 2021
Edited
by admin
on Sat Jun 26 14:34:12 UTC 2021
Record UNII
22VKV8053U
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
RALTEGRAVIR
DASH   EMA EPAR   INN   MART.   MI   VANDF   WHO-DD  
INN  
Official Name English
RALTEGRAVIR [MART.]
Common Name English
RALTEGRAVIR [WHO-DD]
Common Name English
RALTEGRAVIR [VANDF]
Common Name English
MK-0518
Code English
RALTEGRAVIR [MI]
Common Name English
RALTEGRAVIR [EMA EPAR]
Common Name English
N-(4-FLUOROBENZYL)-5-HYDROXY-1-METHYL-2-(1-METHYL-1-(((5-METHYL-1,3,4-OXADIAZOL-2-YL)CARBONYL)AMINO)ETHYL)-6-OXO-1,6-DIHYDROPYRIMIDINE-4-CARBOXAMIDE
Systematic Name English
RALTEGRAVIR [INN]
Common Name English
4-PYRIMIDINECARBOXAMIDE, N-((4-FLUOROPHENYL)METHYL)-1,6-DIHYDRO-5-HYDROXY-1-METHYL-2-(1-METHYL-1-(((5-METHYL-1,3,4-OXADIAZOL-2-YL)CARBONYL)AMINO)ETHYL)-6-OXO-
Systematic Name English
N-(2-(4-(4-FLUOROBENZYLCARBAMOYL)-5-HYDROXY-1-METHYL-6-OXO-1,6- DIHYDROPYRIMIDIN-2-YL)PROPAN-2-YL)-5-METHYL-1,3,4-OXADIAZOLE-2-CARBOXAMIDE
Systematic Name English
Classification Tree Code System Code
NCI_THESAURUS C281
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
WHO-ATC J05AX08
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
NDF-RT N0000175887
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
WHO-ATC J05AR16
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
EMA ASSESSMENT REPORTS ISENTRESS (AUHTORIZED: HIV INFECTIONS)
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
LIVERTOX 830
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
WHO-VATC QJ05AX08
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
NDF-RT N0000000127
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
Code System Code Type Description
EVMPD
SUB25667
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
INN
8842
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
CAS
518048-05-0
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
PUBCHEM
54671008
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
NCI_THESAURUS
C72837
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
MESH
C507898
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
DRUG CENTRAL
2352
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
HSDB
8124
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
LACTMED
Raltegravir
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
MERCK INDEX
M9486
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY Merck Index
EPA CompTox
518048-05-0
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
DRUG BANK
DB06817
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
ChEMBL
CHEMBL254316
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
WIKIPEDIA
RALTEGRAVIR
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
FDA UNII
22VKV8053U
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY
RXCUI
719872
Created by admin on Sat Jun 26 14:34:13 UTC 2021 , Edited by admin on Sat Jun 26 14:34:13 UTC 2021
PRIMARY RxNorm
Related Record Type Details
EXCRETED UNCHANGED
Following administration of a single dose of 200 mg [14 C] raltegravir to young healthy subjects (Protocol 011), approximately 83.0% of the radioactivity dose was recovered, with 51.1% in feces and 31.8% in-urine over a 10-day period.
AMOUNT EXCRETED
URINE
METABOLIC ENZYME -> SUBSTRATE
MAJOR
TARGET ORGANISM->INHIBITOR
TRANSPORTER -> SUBSTRATE
LABELED -> NON-LABELED
TARGET -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
MINOR
BINDER->LIGAND
BINDING
METABOLIC ENZYME -> SUBSTRATE
MINOR
SALT/SOLVATE -> PARENT
Related Record Type Details
METABOLITE INACTIVE -> PARENT
MAJOR
FECAL; URINE
Related Record Type Details
IMPURITY -> PARENT
This is a process impurity controlled in the drug substance and not monitored in the drug product [USP]
IMPURITY -> PARENT
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Tmax PHARMACOKINETIC ORAL ADMINISTRATION

SINGLE DOSE

FASTED CONDITION

Biological Half-life PHARMACOKINETIC Elimination
PHARMACOKINETIC