Raltegravir

Identification

Summary

Raltegravir is an antiretroviral agent used for the treatment of HIV infections in conjunction with other antiretrovirals.

Brand Names
Isentress
Generic Name
Raltegravir
DrugBank Accession Number
DB06817
Background

Raltegravir is an antiretroviral drug produced by Merck & Co., used to treat HIV infection. 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.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 444.4163
Monoisotopic: 444.155746017
Chemical Formula
C20H21FN6O5
Synonyms
  • Raltegravir

Pharmacology

Indication

For the treatment of HIV-1 infection in conjunction with other antiretrovirals.

Pharmacology
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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

Raltegravir inhibits HIV integrase to prevent the viral genome being incorporated into the human genome. Raltegravir is primarily metabolized by glucuronidation.

TargetActionsOrganism
AIntegrase
inhibitor
Human immunodeficiency virus 1
Absorption

Absorbed from the gastrointestinal tract.

Volume of distribution

Approximately 83% bound to human plasma protein and is minimally distributed into red blood cells (blood-to-plasma partitioning ratio of 0.6).

Protein binding

83%

Metabolism

Hepatic (UGT1A1)

Route of elimination

Feces and urine

Half-life

9 hours

Clearance

The major mechanism of clearance of raltegravir in humans is glucuronidation mediated by UGT1A1, the renal clearance of unchanged drug is a minor pathway of elimination of raltegravir (9% of total dose).

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcipimoxThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Raltegravir is combined with Acipimox.
AdenineThe metabolism of Raltegravir can be decreased when combined with Adenine.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Raltegravir.
Alendronic acidThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Alendronic acid is combined with Raltegravir.
AlmasilateThe serum concentration of Raltegravir can be decreased when it is combined with Almasilate.
AluminiumAluminium can cause an increase in the absorption of Raltegravir resulting in an increased serum concentration and potentially a worsening of adverse effects.
Aluminium phosphateAluminium phosphate can cause a decrease in the absorption of Raltegravir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum chlorideAluminum chloride can cause a decrease in the absorption of Raltegravir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of Raltegravir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum oxideAluminum oxide can cause a decrease in the absorption of Raltegravir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Interactions
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Food Interactions
  • Take with or without food.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Raltegravir potassium43Y000U234871038-72-1IFUKBHBISRAZTF-UHFFFAOYSA-M
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
IsentressTablet, chewable100 mgOralMerck Ltd.2013-02-11Not applicableCanada flag
IsentressTablet, film coated400 mg/1OralRemedy Repack2016-07-122016-08-01US flag
IsentressTablet, chewable25 mg/1OralMerck Sharp & Dohme Corp.2011-12-21Not applicableUS flag
IsentressTablet, film coated400 mg/1OralDirect_Rx2019-08-13Not applicableUS flag
IsentressTablet, film coated400 mgOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
IsentressTablet, film coated400 mg/1OralPhysicians Total Care, Inc.2008-04-23Not applicableUS flag00006 0227 61 nlmimage10 a11dd0fe
IsentressTablet, film coated400 mg/1OralNucare Pharmaceuticals,inc.2007-10-12Not applicableUS flag
IsentressTablet, film coated600 mgOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
IsentressTablet, film coated600 mg/1OralMerck Sharp & Dohme Corp.2017-05-26Not applicableUS flag
IsentressTablet, film coated400 mg/1OralREMEDYREPACK INC.2016-08-292018-09-17US flag

Categories

ATC Codes
J05AR16 — Lamivudine and raltegravirJ05AX08 — Raltegravir
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyrimidinecarboxylic acids and derivatives. These are compounds containing a pyrimidine ring which bears a carboxylic acid group (or a derivative thereof).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Pyrimidinecarboxylic acids and derivatives
Alternative Parents
2-heteroaryl carboxamides / Pyrimidones / Fluorobenzenes / Hydroxypyrimidines / Aryl fluorides / Hydropyrimidines / Vinylogous acids / 1,3,4-oxadiazoles / Heteroaromatic compounds / Secondary carboxylic acid amides
show 9 more
Substituents
1,3,4-oxadiazole / 2-heteroaryl carboxamide / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carboxamide group / Carboxylic acid derivative
show 22 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, pyrimidines, 1,2,4-oxadiazole, dicarboxylic acid amide (CHEBI:82960)
Affected organisms
  • Human Immunodeficiency Virus

Chemical Identifiers

UNII
22VKV8053U
CAS number
518048-05-0
InChI Key
CZFFBEXEKNGXKS-UHFFFAOYSA-N
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)
IUPAC Name
N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-2-{2-[(5-methyl-1,3,4-oxadiazol-2-yl)formamido]propan-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide
SMILES
CN1C(=O)C(O)=C(N=C1C(C)(C)NC(=O)C1=NN=C(C)O1)C(=O)NCC1=CC=C(F)C=C1

References

General References
  1. Nachman S, Zheng N, Acosta EP, Teppler H, Homony B, Graham B, Fenton T, Xu X, Wenning L, Spector SA, Frenkel LM, Alvero C, Worrell C, Handelsman E, Wiznia A: Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis. 2014 Feb;58(3):413-22. doi: 10.1093/cid/cit696. Epub 2013 Oct 21. [Article]
  2. Barau C, Furlan V, Yazdanpanah Y, Fagard C, Molina JM, Taburet AM, Barrail-Tran A: Characterization of binding of raltegravir to plasma proteins. Antimicrob Agents Chemother. 2013 Oct;57(10):5147-50. doi: 10.1128/AAC.00625-13. Epub 2013 Jul 15. [Article]
  3. Arora R, de Beauchene IC, Polanski J, Laine E, Tchertanov L: Raltegravir flexibility and its impact on recognition by the HIV-1 IN targets. J Mol Recognit. 2013 Sep;26(9):383-401. doi: 10.1002/jmr.2277. [Article]
  4. Eron JJ, Cooper DA, Steigbigel RT, Clotet B, Gatell JM, Kumar PN, Rockstroh JK, Schechter M, Markowitz M, Yeni P, Loutfy MR, Lazzarin A, Lennox JL, Strohmaier KM, Wan H, Barnard RJ, Nguyen BY, Teppler H: Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis. 2013 Jul;13(7):587-96. doi: 10.1016/S1473-3099(13)70093-8. Epub 2013 May 7. [Article]
  5. Winston A, Mallon PW, Boffito M: The clinical pharmacology of antiretrovirals in development. Expert Opin Drug Metab Toxicol. 2006 Jun;2(3):447-58. [Article]
  6. O'Neal R: MK-0518 and GS-9137: two promising integrase inhibitors in the pipeline. BETA. 2006 Summer;18(4):13-6. [Article]
  7. James JS: Integrase inhibitor MK-0518: Merck opens expanded-access program. AIDS Treat News. 2006 Jul-Sep;(419):5. [Article]
  8. Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H: Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):509-15. [Article]
  9. Colquitt AR, Pham PA: Expanded access drug profile: raltegravir (RAL, MK-0518). Hopkins HIV Rep. 2007 Jan;19(1):11-2. [Article]
  10. Authors unspecified: Raltegravir demonstrates potency. AIDS Patient Care STDS. 2007 Apr;21(4):288. [Article]
  11. Authors unspecified: Anti-HIV agents. Raltegravir--other issues. TreatmentUpdate. 2007 Feb;19(2):9-10. [Article]
  12. Authors unspecified: Anti-HIV agents. Integrase inhibitor raltegravir makes its mark. TreatmentUpdate. 2007 Feb;19(2):8-9. [Article]
  13. Cahn P, Sued O: Raltegravir: a new antiretroviral class for salvage therapy. Lancet. 2007 Apr 14;369(9569):1235-6. [Article]
KEGG Drug
D06676
PubChem Compound
54671008
PubChem Substance
175427095
ChemSpider
16445111
BindingDB
25351
RxNav
719872
ChEMBL
CHEMBL254316
ZINC
ZINC000013831130
PDBe Ligand
RLT
Drugs.com
Drugs.com Drug Page
Wikipedia
Raltegravir
PDB Entries
3l2v / 3oya / 4mda / 4mdb / 7lw6 / 7oug
FDA label
Download (127 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableHealthy Subjects (HS)1
4CompletedBasic ScienceHepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV) Infections1
4CompletedHealth Services ResearchHuman Immunodeficiency Virus (HIV) Infections1
4CompletedPreventionHuman Immunodeficiency Virus (HIV) Infections6
4CompletedTreatmentAdverse Drug Reaction (ADR) / Human Immunodeficiency Virus (HIV) Infections / Quality of Life (QOL)1
4CompletedTreatmentAging-related Inflammation in HIV-infected Patients1
4CompletedTreatmentCardiovascular Disease (CVD) / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentCardiovascular Disease (CVD) / Human Immunodeficiency Virus (HIV) Infections / Inflammation1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentFatty Liver / HIV Seropositivity / Syndrome, Metabolic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral
Granule, for suspensionOral100 MG
Granule, for suspensionOral100 mg/1
TabletOral100 MG
TabletOral25 MG
TabletOral400 mg
Tablet, chewableOral100 mg/1
Tablet, chewableOral25 mg/1
Tablet, film coatedOral400 mg/1
Tablet, film coatedOral400 MG
Tablet, film coatedOral600 mg/1
Tablet, film coatedOral600 MG
Tablet, film coatedOral
Tablet, chewableOral100 mg
Tablet, chewableOral25 mg
TabletOral600 mg
GranuleOral100 mg
PowderNot applicable1 kg/1kg
Tablet, coatedOral400 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7217713Yes2007-05-152023-04-21US flag
US7435734Yes2008-10-142023-04-21US flag
US7754731Yes2010-07-132029-09-11US flag
US7169780Yes2007-01-302024-04-03US flag
US7820660No2010-10-262023-04-25US flag
US9649311Yes2017-05-162031-04-21US flag
US10772888No2020-09-152032-03-30US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP-0.39ChemAxon
pKa (Strongest Acidic)5.62ChemAxon
pKa (Strongest Basic)-1.5ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area150.02 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity112.59 m3·mol-1ChemAxon
Polarizability42.47 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-01ot-0417900000-7f0f52f17ac409473482
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-0011900000-1f750fd89ed368c2519a

Targets

Drugtargets2
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Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q7ZJM1
Uniprot Name
Integrase
Molecular Weight
32226.645 Da
References
  1. Evering TH, Markowitz M: Raltegravir: an integrase inhibitor for HIV-1. Expert Opin Investig Drugs. 2008 Mar;17(3):413-22. doi: 10.1517/13543784.17.3.413 . [Article]
  2. Anker M, Corales RB: Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs. 2008 Jan;17(1):97-103. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Wenning LA, Petry AS, Kost JT, Jin B, Breidinger SA, DeLepeleire I, Carlini EJ, Young S, Rushmore T, Wagner F, Lunde NM, Bieberdorf F, Greenberg H, Stone JA, Wagner JA, Iwamoto M: Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms. Clin Pharmacol Ther. 2009 Jun;85(6):623-7. doi: 10.1038/clpt.2009.12. Epub 2009 Mar 11. [Article]
  2. Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B, Mangin E, Marbury TC, Berg JK, Chodakewitz JA, Stone JA, Gottesdiener KM, Wagner JA, Iwamoto M: Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2009 Jul;53(7):2852-6. doi: 10.1128/AAC.01468-08. Epub 2009 May 11. [Article]
  3. Anker M, Corales RB: Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs. 2008 Jan;17(1):97-103. [Article]

Drug created on September 14, 2010 16:21 / Updated on October 22, 2021 23:18