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 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

1192147200000
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:
healthy, 29 +/- 13
Health Status: healthy
Age Group: 29 +/- 13
Sex: M+F
Sources:
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:
healthy, 29 +/- 13
Health Status: healthy
Age Group: 29 +/- 13
Sex: M+F
Sources:
24000 mg single, oral
Overdose
Dose: 24000 mg
Route: oral
Route: single
Dose: 24000 mg
Sources:
unhealthy, 42
Health Status: unhealthy
Age Group: 42
Sex: M
Sources:
Disc. AE: Nausea, Abdominal pain...
AEs leading to
discontinuation/dose reduction:
Nausea (mild)
Abdominal pain
Sources:
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:
unhealthy
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:
AEs

AEs

AESignificanceDosePopulation
Abdominal pain Disc. AE
24000 mg single, oral
Overdose
Dose: 24000 mg
Route: oral
Route: single
Dose: 24000 mg
Sources:
unhealthy, 42
Health Status: unhealthy
Age Group: 42
Sex: M
Sources:
Nausea mild
Disc. AE
24000 mg single, oral
Overdose
Dose: 24000 mg
Route: oral
Route: single
Dose: 24000 mg
Sources:
unhealthy, 42
Health Status: unhealthy
Age Group: 42
Sex: M
Sources:
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:
unhealthy
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:
unhealthy
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:
unhealthy
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:
unhealthy
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:
unhealthy
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Raltegravir susceptibility and fitness progression of HIV type-1 integrase in patients on long-term antiretroviral therapy.
2008
HIV infection in the elderly.
2008
"One pill, once daily": what clinicians need to know about Atriplatrade mark.
2008 Apr
Raltegravir: first in class HIV integrase inhibitor.
2008 Apr
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
A conventional LC-MS method developed for the determination of plasma raltegravir concentrations.
2008 Aug
Raltegravir, an HIV-1 integrase inhibitor for HIV infection.
2008 Aug
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
Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors.
2008 Aug 7
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
Integrase inhibitors for the treatment of HIV infection.
2008 Jul
How developing world concerns need to be part of drug development plans: a case study of four emerging antiretrovirals.
2008 Jul
Atazanavir modestly increases plasma levels of raltegravir in healthy subjects.
2008 Jul 1
Severe rhabdomyolysis associated with raltegravir use.
2008 Jul 11
Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.
2008 Jul 24
Raltegravir with optimized background therapy for resistant HIV-1 infection.
2008 Jul 24
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 treatment response in an HIV-2 infected patient: a case report.
2008 May 31
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
Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection.
2008 Nov
Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants.
2008 Nov
Elevated alkaline phosphatase with raltegravir in a treatment experienced HIV patient.
2008 Nov 12
An accurate and precise high-performance liquid chromatography method for the rapid quantification of the novel HIV integrase inhibitor raltegravir in human blood plasma after solid phase extraction.
2008 Nov 3
Raltegravir for postexposure prophylaxis following occupational exposure to HIV.
2008 Nov 30
Raltegravir: the first HIV integrase inhibitor.
2008 Oct
[New CCR5 inhibitor antiretroviral drugs and integrase inhibitors].
2008 Oct
Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy.
2008 Oct
Emerging resistance profiles of newly approved antiretroviral drugs.
2008 Oct-Nov
Clade-specific HIV-1 integrase polymorphisms do not reduce raltegravir and elvitegravir phenotypic susceptibility.
2008 Sep 12
Exacerbation of depression associated with starting raltegravir: a report of four cases.
2008 Sep 12
Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection.
2008 Sep 25
Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants.
2008 Sep 9
Comparing two integrase inhibitors. The first head-to-head study comparing raltegravir and elvitegravir.
2008 Sep-Oct
Emerging pharmacology: inhibitors of human immunodeficiency virus integration.
2009
Quantitative prediction of human clearance guiding the development of Raltegravir (MK-0518, isentress) and related HIV integrase inhibitors.
2009 Apr
Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV.
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
Quantification of the HIV-integrase inhibitor raltegravir and detection of its main metabolite in human plasma, dried blood spots and peripheral blood mononuclear cell lysate by means of high-performance liquid chromatography tandem mass spectrometry.
2009 Feb 20
Implications of HIV-1 M group polymorphisms on integrase inhibitor efficacy and resistance: genetic and structural in silico analyses.
2009 Jan 13
Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase.
2009 Mar
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
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