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Identification
NameDolutegravir
Accession NumberDB08930
TypeSmall Molecule
GroupsApproved
Description

Dolutegravir is indicated for HIV-1 infection for adults and children and adolescents ≥12 years of age and weighing ≥40 kg. It is marketed as Tivicay as dolutegravir sodium. 52.6 mg of dolutegravir sodium is equivalent to 50 mg dolutegravir free acid. FDA approved on August 12, 2013.

Structure
Thumb
SynonymsNot Available
External Identifiers
  • GSK572
  • S-349572
  • S/GSK1349572
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Tivicaytablet, film coated50 mg/1oralVii V Healthcare Company2013-08-13Not applicableUs
Tivicaytablet50 mgoralViiv Healthcare Ulc2013-11-08Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
TriumeqVii V Healthcare Company
Salts
Name/CASStructureProperties
Dolutegravir Sodium
ThumbNot applicableDBSALT000943
Categories
UNIIDKO1W9H7M1
CAS number1051375-16-6
WeightAverage: 419.3788
Monoisotopic: 419.129277143
Chemical FormulaC20H19F2N3O5
InChI KeyInChIKey=RHWKPHLQXYSBKR-PJJZDBKBNA-N
InChI
InChI=1/C20H19F2N3O5/c1-10-4-5-30-15-9-24-8-13(17(26)18(27)16(24)20(29)25(10)15)19(28)23-7-11-2-3-12(21)6-14(11)22/h2-3,6,8,10,15,27H,4-5,7,9H2,1H3,(H,23,28)/t10-,15+/s2
IUPAC Name
(3S,7R)-N-[(2,4-difluorophenyl)methyl]-11-hydroxy-7-methyl-9,12-dioxo-4-oxa-1,8-diazatricyclo[8.4.0.0³,⁸]tetradeca-10,13-diene-13-carboxamide
SMILES
[H][C@]12CN3C=C(C(=O)NCC4=CC=C(F)C=C4F)C(=O)C(O)=C3C(=O)N1[[email protected]](C)CCO2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyridinecarboxylic acids and derivatives. These are compounds containing a pyridine ring bearing a carboxylic acid group or a derivative thereof.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPyridines and derivatives
Sub ClassPyridinecarboxylic acids and derivatives
Direct ParentPyridinecarboxylic acids and derivatives
Alternative Parents
Substituents
  • Pyridine carboxylic acid or derivatives
  • Phenylmethylamine
  • Benzylamine
  • Hydroxypyridine
  • Halobenzene
  • Fluorobenzene
  • Benzenoid
  • Oxazinane
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • 1,3-oxazinane
  • Heteroaromatic compound
  • Vinylogous amide
  • Vinylogous acid
  • Cyclic ketone
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Lactam
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationDolutegravir is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children aged 12 years and older and weighing at least 40 kg.
PharmacodynamicsHIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent antiviral activity with mean declines from baseline to Day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. Antiviral response was maintained for 3 to 4 days after the last 50 mg dose. Dolutegravir did not prolong the QTc interval over 24 hours postdose. The maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Those given a 50 mg once daily dose of dolutegravir also experienced a decrease in creatinine clearance as determined by 24-hour urine collection after 14 days. There is no significant effect on actual glomerular filtration rate or renal plasma flow compared to placebo.
Mechanism of actionDolutegravir is an HIV-1 antiviral agent. It inhibits HIV integrase by binding to the active site and blocking the strand transfer step to retroviral DNA integration. This is an essential step of the HIV replication cycle and will result in an inhibition of viral activity. Dolutegravir has a mean EC50 value of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.
Related Articles
AbsorptionWhen 50 mg of dolutegravir once daily was orally administered to HIV-1 infected adults, the AUC (0-24), Cmax, and Cmin is 53.6 mcg.h/mL, 3.67 mcg/mL, and 1.11 mcg/mL, respectively. The peak plasma concentration was observed 2 to 3 hours post dose. Steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1.2 to 1.5. When 50 mg once daily is given to pediatric patients (12 to <18 years and weighing ≥40 kg) the Cmax, AUC (0-24), and C24 is 3.49 mcg/mL, 46 mcg.h/mL, and 0.90 mcg/mL respectively.
Volume of distribution

Volume of distribution (Vd/F), 50 mg once daily = 17.4 L.
The median dolutegravir concentration in the CSF was 18 ng/mL after 2 weeks of treatment.

Protein bindingDolutegravir is highly protein bound (≥98.9%) to human plasma proteins.
Metabolism

Dolutegravir is primarily metabolized by UGT1A1 with some minor contributed CYP3A.

Route of eliminationWhen a single oral dose of dolutegravir is given, 53% was excreted unchanged in the feces. 31% is excreted in urine in which consists of the ether glucuronide of dolutegravir (18.9%), a metabolite formed by oxidation at the benzylic carbon (3.0%), and its hydrolytic N-dealkylation product (3.6%). Renal elimination of unchanged drug was low (<1%).
Half lifeTerminal half life = 14 hours
Clearance

Apparent clearance (CL/F) = 1.0 L/h

ToxicityThe most common adverse reactions of moderate to severe intensity and incidence ≥2% (in those receiving TIVICAY in any one adult trial) are insomnia and headache.
Affected organisms
  • Human Immunodeficiency Virus
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral50 mg
Tablet, film coatedoral50 mg/1
Tabletoral
Tablet, film coatedoral
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5905082 Yes1996-11-182016-11-18Us
US6294540 Yes1998-11-142018-11-14Us
US6417191 Yes1996-09-282016-09-28Us
US8129385 No2007-10-052027-10-05Us
US9242986 No2009-10-082029-10-08Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilitySlightly solubleFDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0922 mg/mLALOGPS
logP0.98ALOGPS
logP1.1ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)8.7ChemAxon
pKa (Strongest Basic)0.28ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.18 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity102.77 m3·mol-1ChemAxon
Polarizability39.99 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC: Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010 Jan;54(1):254-8. doi: 10.1128/AAC.00842-09. Epub 2009 Nov 2. [PubMed:19884365 ]
  2. Lenz JC, Rockstroh JK: S/GSK1349572, a new integrase inhibitor for the treatment of HIV: promises and challenges. Expert Opin Investig Drugs. 2011 Apr;20(4):537-48. doi: 10.1517/13543784.2011.562189. Epub 2011 Mar 8. [PubMed:21381981 ]
  3. Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, Stroder R, Chen S, Underwood M, Fujiwara T, Piscitelli S, Lalezari J: Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011 Sep 10;25(14):1737-45. doi: 10.1097/QAD.0b013e32834a1dd9. [PubMed:21716073 ]
  4. Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P: Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. doi: 10.1124/mol.111.073189. Epub 2011 Jun 30. [PubMed:21719464 ]
  5. Katlama C, Murphy R: Dolutegravir for the treatment of HIV. Expert Opin Investig Drugs. 2012 Apr;21(4):523-30. doi: 10.1517/13543784.2012.661713. Epub 2012 Mar 2. [PubMed:22380682 ]
  6. Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D, Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B, Dorey D, Underwood M, Griffith S, Min S: Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013 Aug 24;382(9893):700-8. doi: 10.1016/S0140-6736(13)61221-0. Epub 2013 Jul 3. [PubMed:23830355 ]
  7. Authors unspecified: Dolutegravir (Tivicay) for HIV. Med Lett Drugs Ther. 2013 Sep 30;55(1426):77-9. [PubMed:24081387 ]
  8. Cottrell ML, Hadzic T, Kashuba AD: Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013 Nov;52(11):981-94. doi: 10.1007/s40262-013-0093-2. [PubMed:23824675 ]
  9. Ballantyne AD, Perry CM: Dolutegravir: first global approval. Drugs. 2013 Sep;73(14):1627-37. doi: 10.1007/s40265-013-0121-4. [PubMed:24052331 ]
  10. Boyd MA, Donovan B: Antiretroviral therapy: dolutegravir sets SAIL(ING). Lancet. 2013 Aug 24;382(9893):664-6. doi: 10.1016/S0140-6736(13)61456-7. Epub 2013 Jul 3. [PubMed:23830358 ]
External Links
ATC CodesJ05AR13J05AX12
AHFS Codes
  • 8:18.08.12
PDB EntriesNot Available
FDA labelDownload (332 KB)
MSDSDownload (61.6 KB)
Interactions
Drug Interactions
Drug
Aluminum hydroxideThe serum concentration of Dolutegravir can be decreased when it is combined with Aluminum hydroxide.
Calcium AcetateThe serum concentration of Dolutegravir can be decreased when it is combined with Calcium Acetate.
Calcium carbonateThe serum concentration of Dolutegravir can be decreased when it is combined with Calcium carbonate.
Calcium ChlorideThe serum concentration of Dolutegravir can be decreased when it is combined with Calcium Chloride.
Calcium citrateThe serum concentration of Dolutegravir can be decreased when it is combined with Calcium citrate.
Calcium gluconateThe serum concentration of Dolutegravir can be decreased when it is combined with Calcium gluconate.
CarbamazepineThe serum concentration of Dolutegravir can be decreased when it is combined with Carbamazepine.
DofetilideThe serum concentration of Dofetilide can be increased when it is combined with Dolutegravir.
EfavirenzThe serum concentration of Dolutegravir can be decreased when it is combined with Efavirenz.
EtravirineThe serum concentration of Dolutegravir can be decreased when it is combined with Etravirine.
Ferric CitrateThe serum concentration of Dolutegravir can be decreased when it is combined with Ferric Citrate.
FosamprenavirThe serum concentration of Dolutegravir can be decreased when it is combined with Fosamprenavir.
FosphenytoinThe serum concentration of Dolutegravir can be decreased when it is combined with Fosphenytoin.
Iron DextranThe serum concentration of Dolutegravir can be decreased when it is combined with Iron Dextran.
Magnesium chlorideThe serum concentration of Dolutegravir can be decreased when it is combined with Magnesium chloride.
Magnesium citrateThe serum concentration of Dolutegravir can be decreased when it is combined with Magnesium citrate.
Magnesium hydroxideThe serum concentration of Dolutegravir can be decreased when it is combined with Magnesium hydroxide.
Magnesium oxideThe serum concentration of Dolutegravir can be decreased when it is combined with Magnesium oxide.
Magnesium salicylateThe serum concentration of Dolutegravir can be decreased when it is combined with Magnesium salicylate.
Magnesium SulfateThe serum concentration of Dolutegravir can be decreased when it is combined with Magnesium Sulfate.
MetforminThe serum concentration of Metformin can be increased when it is combined with Dolutegravir.
NevirapineThe serum concentration of Dolutegravir can be decreased when it is combined with Nevirapine.
OxcarbazepineThe serum concentration of Dolutegravir can be decreased when it is combined with Oxcarbazepine.
PhenobarbitalThe serum concentration of Dolutegravir can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Dolutegravir can be decreased when it is combined with Phenytoin.
PrimidoneThe serum concentration of Dolutegravir can be decreased when it is combined with Primidone.
RifampicinThe serum concentration of Dolutegravir can be decreased when it is combined with Rifampicin.
SeleniumThe serum concentration of Dolutegravir can be decreased when it is combined with Selenium.
St. John's WortThe serum concentration of Dolutegravir can be decreased when it is combined with St. John&#39;s Wort.
SucralfateThe serum concentration of Dolutegravir can be decreased when it is combined with Sucralfate.
TipranavirThe serum concentration of Dolutegravir can be decreased when it is combined with Tipranavir.
ZincThe serum concentration of Dolutegravir can be decreased when it is combined with Zinc.
Zinc gluconateThe serum concentration of Dolutegravir can be decreased when it is combined with Zinc gluconate.
Zinc sulfateThe serum concentration of Dolutegravir can be decreased when it is combined with Zinc sulfate.
Food InteractionsNot Available

Targets

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
Molecular Weight:
32226.645 Da
References
  1. Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P: Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. doi: 10.1124/mol.111.073189. Epub 2011 Jun 30. [PubMed:21719464 ]
  2. Waki K, Sugawara Y: Implications of integrase inhibitors for HIV-infected transplantation recipients: raltegravir and dolutegravir (S/GSK 1349572). Biosci Trends. 2011;5(5):189-91. [PubMed:22101373 ]
  3. Underwood MR, Johns BA, Sato A, Martin JN, Deeks SG, Fujiwara T: The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):297-301. doi: 10.1097/QAI.0b013e31826bfd02. [PubMed:22878423 ]
  4. Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, Peppercorn A, Everts S, Piscitelli S, Flexner C: Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):21-7. doi: 10.1097/QAI.0b013e318276cda9. [PubMed:23075918 ]
  5. Cottrell ML, Hadzic T, Kashuba AD: Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013 Nov;52(11):981-94. doi: 10.1007/s40262-013-0093-2. [PubMed:23824675 ]
  6. Rathbun RC, Lockhart SM, Miller MM, Liedtke MD: Dolutegravir, a second-generation integrase inhibitor for the treatment of HIV-1 infection. Ann Pharmacother. 2014 Mar;48(3):395-403. doi: 10.1177/1060028013513558. Epub 2013 Nov 19. [PubMed:24259658 ]

Enzymes

Kind
Protein
Organism
Human
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 IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4-methylumbelliferone, 1-naph...
Gene Name:
UGT1A1
Uniprot ID:
P22309
Molecular Weight:
59590.91 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Transcriptional activator activity, rna polymerase ii core promoter proximal region sequence-specific binding
Specific Function:
Transcription factor that specifically binds to the octamer motif (5'-ATTTGCAT-3'). Regulates transcription in a number of tissues in addition to activating immunoglobulin gene expression. Modulates transcription transactivation by NR3C1, AR and PGR. Isoform 5 activates the U2 small nuclear RNA (snRNA) promoter.
Gene Name:
POU2F2
Uniprot ID:
P09086
Molecular Weight:
51208.51 Da
Kind
Protein group
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Components:
NameUniProt IDDetails
Cytochrome P450 3A4P08684 Details
Cytochrome P450 3A43Q9HB55 Details
Cytochrome P450 3A5P20815 Details
Cytochrome P450 3A7P24462 Details
Comments
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Drug created on November 11, 2013 14:17 / Updated on July 01, 2016 03:05