Cabotegravir

Identification

Summary

Cabotegravir is an HIV-1 integrase inhibitor.

Brand Names
Vocabria
Generic Name
Cabotegravir
DrugBank Accession Number
DB11751
Background

Cabotegravir, or GSK1265744, is an HIV-1 integrase inhibitor that is prescribed with the non-nucleoside reverse transcriptase inhibitor, rilpivirine.4,5,6 Early research into cabotegravir showed it had lower oral bioavailability than dolutegravir.4 The devlopment of cabotegravir was later developed to create a long acting monthly intramuscular injection.4,6

Cabotegravir was granted FDA approval on 21 January 2021.7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 405.358
Monoisotopic: 405.113626985
Chemical Formula
C19H17F2N3O5
Synonyms
  • Cabotegravir
External IDs
  • 744 LA
  • GSK 1265744
  • GSK 744
  • GSK-1265744A
  • GSK1265744
  • GSK1265744A
  • GSK744
  • GSK744 LA
  • GSK744 LAP
  • S-265744
  • S/GSK1265744

Pharmacology

Indication

Oral cabotegravir is indicated in combination with rilpivirine for the short term treatment of HIV-1 in virologically suppressed adults with no history of treatment failure to assess tolerability of cabotegravir or who have missed an injected dose of cabotegravir.5 Intramuscular extended-release cabotegravir is indicated in combination with rilpivirine as a complete regimen for virologically suppressed adults with no history of treatment failure.6 The intramuscular form is meant to replace their current antiretroviral treatment.6

Pharmacology
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Drug Discovery
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Cabotegravir is an inhibitor of HIV integrase, which reduces viral replication.5,6 It has a long duration of action as the oral tablet is given daily and the intramuscular suspension is given monthly.5,6 Patients should be counselled regarding the risk of hypersensitivity, hepatotoxicity, and depression.5,6

Mechanism of action

Cabotegravir binds to the active site of HIV integrase, preventing strand transfer of the viral genome into the host genome, and preventing replication of the virus.5,6

TargetActionsOrganism
AIntegrase
inhibitor
Human immunodeficiency virus 1
Absorption

Oral cabotegravir has a Tmax of 3 hours, reaches a Cmax of 8.0 µg/mL, and has an AUC of 145 µg*h/mL.5 Intramuscular extended-release cabotegravir has a Tmax of 7 days, reaches a Cmax of 8.0 µg/mL, and has an AUC of 1591 µg*h/mL.6

Volume of distribution

Data regarding the volume of distribution of cabotegravir is not readily available.3,6,8

Protein binding

Cabotegravir is >99.8% bound to proteins in plasma, usually alubmin.5

Metabolism

Cabotegravir is O-glucuronidated to the M1 and M2 metabolites, with 67% of glucuronidation performed by UGT1A1, and 33% by UGT1A9.1,2

Hover over products below to view reaction partners

Route of elimination

An oral radiolabelled dose of cabotegravir is 58.5% recovered in the feces and 26.8% recovered in the urine.1,2,5

Half-life

The mean half life of oral cabotegravir is 41 hours.5 The mean half life of intramuscular extended-release cabotegravir is 5.6-11.5 weeks.6

Clearance

Data regarding the clearance of cabotegravir is not readily available.3,6,8 Clearance in dogs was 0.34 mL/min/kg and in cynomolgus monkeys was 0.32 mL/min/kg.4

Adverse Effects
Medicalerrors
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Toxicity

Data regarding the toxicity of cabotegravir is not readily available.5,6,8 In the event of overdose, patients should have their vital signs monitored, including an ECG to monitor the QT interval.5,6 Treat patients symptomatically and supportively.5,6 As cabotegravir is highly protein bound, dialysis is not expected to remove a significant amount of the drug from plasma.5,6

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
AcamprosateThe excretion of Acamprosate can be decreased when combined with Cabotegravir.
AcyclovirThe excretion of Acyclovir can be decreased when combined with Cabotegravir.
Adefovir dipivoxilThe excretion of Adefovir dipivoxil can be decreased when combined with Cabotegravir.
AdenineThe metabolism of Cabotegravir 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 Cabotegravir.
AllopurinolThe excretion of Allopurinol can be decreased when combined with Cabotegravir.
AlprostadilThe excretion of Alprostadil can be decreased when combined with Cabotegravir.
Aminohippuric acidThe excretion of Aminohippuric acid can be decreased when combined with Cabotegravir.
AmitriptylineThe metabolism of Cabotegravir can be decreased when combined with Amitriptyline.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Cabotegravir.
Interactions
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Food Interactions
  • Take at the same time every day. Take the oral tablets at the same time every day.
  • Take with food. Take the oral tablets with a meal.

Products

Products
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Product Ingredients
IngredientUNIICASInChI Key
Cabotegravir sodium3L12PT535M1051375-13-3AEZBWGMXBKPGFP-KIUAEZIZSA-M
International/Other Brands
Vocabria (ViiV Healthcare)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Vocabria400 mgIntramuscularVii V Healthcare B.V.2021-02-08Not applicableEU flag
VocabriaTablet, film coated30 mgOralVii V Healthcare B.V.2021-02-08Not applicableEU flag
VocabriaTablet30 mgOralViiV Healthcare ULC2020-09-21Not applicableCanada flag
Vocabria600 mgIntramuscularVii V Healthcare B.V.2021-02-08Not applicableEU flag
VocabriaTablet, film coated30 mg/1OralViiV Healthcare Company2021-01-21Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
CabenuvaCabotegravir (200 mg / mL) + Rilpivirine (300 mg / mL)Kit; Suspension, extended releaseIntramuscularViiV Healthcare ULC2020-09-21Not applicableCanada flag
CabenuvaCabotegravir (200 mg/1mL) + Rilpivirine (300 mg/1mL)Kit; Suspension, extended releaseIntramuscularViiV Healthcare Company2021-01-21Not applicableUS flag
CabenuvaCabotegravir (200 mg / mL) + Rilpivirine (300 mg / mL)Kit; Suspension, extended releaseIntramuscularViiV Healthcare ULC2020-09-21Not applicableCanada flag
CabenuvaCabotegravir (200 mg/1mL) + Rilpivirine (300 mg/1mL)Kit; Suspension, extended releaseIntramuscularViiV Healthcare Company2021-01-21Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Pyridinecarboxylic acids and derivatives
Direct Parent
Pyridinecarboxylic acids and derivatives
Alternative Parents
2-heteroaryl carboxamides / Fluorobenzenes / Hydroxypyridines / Aryl fluorides / Vinylogous amides / Vinylogous acids / Tertiary carboxylic acid amides / Heteroaromatic compounds / Oxazolidines / Lactams
show 8 more
Substituents
2-heteroaryl carboxamide / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carboxamide group / Carboxylic acid derivative / Cyclic ketone / Fluorobenzene
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
HMH0132Z1Q
CAS number
1051375-10-0
InChI Key
WCWSTNLSLKSJPK-LKFCYVNXSA-N
InChI
InChI=1S/C19H17F2N3O5/c1-9-8-29-14-7-23-6-12(16(25)17(26)15(23)19(28)24(9)14)18(27)22-5-10-2-3-11(20)4-13(10)21/h2-4,6,9,14,26H,5,7-8H2,1H3,(H,22,27)/t9-,14+/m0/s1
IUPAC Name
(3R,6S)-N-[(2,4-difluorophenyl)methyl]-10-hydroxy-6-methyl-8,11-dioxo-4-oxa-1,7-diazatricyclo[7.4.0.0^{3,7}]trideca-9,12-diene-12-carboxamide
SMILES
[H][C@@]12CN3C=C(C(=O)NCC4=C(F)C=C(F)C=C4)C(=O)C(O)=C3C(=O)N1[C@@H](C)CO2

References

General References
  1. Bowers GD, Culp A, Reese MJ, Tabolt G, Moss L, Piscitelli S, Huynh P, Wagner D, Ford SL, Gould EP, Pan R, Lou Y, Margolis DA, Spreen WR: Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans. Xenobiotica. 2016;46(2):147-62. doi: 10.3109/00498254.2015.1060372. Epub 2015 Jul 1. [Article]
  2. Patel M, Eberl HC, Wolf A, Pierre E, Polli JW, Zamek-Gliszczynski MJ: Mechanistic Basis of Cabotegravir-Glucuronide Disposition in Humans. J Pharmacol Exp Ther. 2019 Aug;370(2):269-277. doi: 10.1124/jpet.119.258384. Epub 2019 Jun 7. [Article]
  3. Spreen W, Min S, Ford SL, Chen S, Lou Y, Bomar M, St Clair M, Piscitelli S, Fujiwara T: Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin Trials. 2013 Sep-Oct;14(5):192-203. doi: 10.1310/hct1405-192. [Article]
  4. Johns BA, Kawasuji T, Weatherhead JG, Taishi T, Temelkoff DP, Yoshida H, Akiyama T, Taoda Y, Murai H, Kiyama R, Fuji M, Tanimoto N, Jeffrey J, Foster SA, Yoshinaga T, Seki T, Kobayashi M, Sato A, Johnson MN, Garvey EP, Fujiwara T: Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J Med Chem. 2013 Jul 25;56(14):5901-16. doi: 10.1021/jm400645w. Epub 2013 Jul 11. [Article]
  5. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]
  6. FDA Approved Drug Products: Cabenuva (Cabotegravir and Rilpivirine) Intramuscular Extended-Release Suspension [Link]
  7. FDA News Release: FDA Approves First Extended-Release, Injectable Drug Regimen for Adults Living with HIV [Link]
  8. Cayman Chemical: Cabotegravir MSDS [Link]
PubChem Compound
54713659
PubChem Substance
347828108
ChemSpider
30829503
BindingDB
50492496
RxNav
2475077
ChEMBL
CHEMBL2403238
ZINC
ZINC000096927633
Wikipedia
Cabotegravir
AHFS Codes
  • 08:18.08 — Antiretrovirals

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis (TB)1
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections3
3RecruitingPreventionHuman Immunodeficiency Virus (HIV) Infections1
3RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections2
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2CompletedPreventionHuman Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections3
2RecruitingPreventionHuman Immunodeficiency Virus (HIV) Infections2
2RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2WithdrawnPreventionHuman Immunodeficiency Virus (HIV) Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Kit; suspension, extended releaseIntramuscular
TabletOral30 mg
Tablet, film coatedOral30 mg/1
Tablet, film coatedOral30 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7125879No2006-10-242022-08-09US flag
US6838464No2005-01-042021-02-26US flag
US8080551No2011-12-202023-04-11US flag
US8410103No2006-04-282026-04-28US flag
US10927129No2006-04-282026-04-28US flag

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP1.04ChemAxon
pKa (Strongest Acidic)10.04ChemAxon
pKa (Strongest Basic)-0.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.18 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity97.9 m3·mol-1ChemAxon
Polarizability38.11 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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

Targets

Drugtargets
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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. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]

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. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Shaik JSB, Ford SL, Lou Y, Zhang Z, Bakshi KK, Tenorio AR, Trezza C, Spreen WR, Patel P: A Phase 1 Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Patients With Hepatic Impairment and Healthy Matched Controls. Clin Pharmacol Drug Dev. 2019 Jul;8(5):664-673. doi: 10.1002/cpdd.655. Epub 2019 Feb 27. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. OAT1 and OAT3 (organic anion transporters 1 and 3) [Link]
  2. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. OAT1 and OAT3 (organic anion transporters 1 and 3) [Link]
  2. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Vocabria (Cabotegravir) Oral Tablets [Link]

Drug created on October 20, 2016 20:45 / Updated on June 18, 2021 14:14