Bictegravir

Identification

Name

Bictegravir

Accession Number

DB11799

Description

Bictegravir is a recently approved investigational drug that has been used in trials studying the treatment of HIV-1 and HIV-2 infection. It has been approved for HIV-1 monotherapy combined with 2 other antiretrovirals in a single tablet.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Bictegravir (DB11799)

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Weight

Average: 449.386
Monoisotopic: 449.119855181

Chemical Formula

C₂₁H₁₈F₃N₃O₅

Synonyms

• Bictegravir

External IDs

• GS-9883
• GS-9883-01

Pharmacology

Indication

Bictegravir is indicated in the management of HIV-1 infection in patients not previously treated with antiretroviral therapy. Additionally, Bictegravir is indicated in the management of HIV-1 infection in patients who are virologically suppressed (HIV-1 RNA <50 c/mL) on a regular antiretroviral regimen for a minimum of three months without a history of failure in treatment and no known factors associated with the resistance to the individual components of the medication. It is used in combination with tenofovir and emtricitabine ^3,4.

Associated Conditions

• Stable antiretroviral regimen, less than 50 HIV-1 RNA copies HIV-1
• Untreated with antiretrovirals HIV-1

Contraindications & Blackbox Warnings

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Pharmacodynamics

Bictegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Bictegravir (BIC) inhibits HIV-1 virus replication into the human genome. It can be taken once daily without additional dosing ^2,3,4,5. Bictegravir (BIC) inhibits strand transfer of viral DNA into the host genome and thereby prevents HIV-1 replication ⁵.

Mechanism of action

This single dose medication inhibits the strand transfer of viral DNA into the human genome, preventing HIV-1 virus replication and propagation ².

In vitro, bictegravir has shown powerful antiviral activity against HIV-2 and various subtypes of HIV-1. It has shown synergistic effects when combined with other ARVs, including tenofovir alafenamide (TAF), emtricitabine (FTC), and darunavir (DRV) ^Label. The three components of the first USA approved medication ( trade name: Biktarvy ) are as follows:

Bictegravir: integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme necessary for viral replication. Inhibition of the integrase enzyme prevents the integration of HIV-1 into host DNA, blocking the conversion of the HIV-1 provirus and progression of the virus ^Label.

Emtricitabine: FTC, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine is phosphorylated to form emtricitabine 5'-triphosphate intracellularly. This metabolite inhibits the activity of human immunodeficiency virus (HIV) reverse transcriptase by competing with the substrate deoxycytidine 5'-triphosphate and by incorporating itself into viral DNA preventing DNA chain elongation ^Label.

Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2′-deoxyadenosine monophosphate analog). Plasma exposure to TAF leads to leakage into cells and then TAF is intracellularly converted to tenofovir by hydrolysis by cathepsin. Tenofovir is subsequently phosphorylated by cellular kinases to the metabolite tenofovir diphosphate, which is the active form of the drug. Tenofovir diphosphate inhibits HIV-1 replication by incorporating into viral DNA by the HIV reverse transcriptase, resulting in DNA chain-termination. Tenofovir diphosphate also weakly inhibits mammalian DNA polymerases ^Label.

Target	Actions	Organism
AReverse transcriptase/RNaseH	antagonist	Human immunodeficiency virus 1
AIntegrase	antagonist	Human immunodeficiency virus 1

Absorption

Bictegravir is rapidly absorbed within the body. Tmax= 2.0-4.0h ^Label

Volume of distribution

0.2 L/Kg in humans ²

Protein binding

> 99 % bound to human plasma Blood to plasma ratio: 0.64 ^Label,2

Metabolism

In a 10-day dose-ranging study, monotherapy (5 mg to 100 mg) once daily in adults who were not previously treated with bictegravir, the median half-life of BIC ranged from 15.9 h - 20.9 h ^3,Label.

Route of elimination

BIC is mainly eliminated through UGT1A1 glucuronidation and CYP3A4 oxidation, equally ². About 1% of the bictegravir dose is excreted in the urine, unchanged [1218,1219].

Half-life

1. 3h ^Label,3

Clearance

Bictegravir is mainly cleared by the kidneys. Those with renal clearance <30 should not take bictegravir ^Label

Adverse Effects

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Toxicity

Those with renal disease and creatinine clearance of <30 mL/min should not take bictegravir ^Label. Patients with hepatic disease should not take bictegravir.

Most common adverse reactions include diarrhea, nausea, and headache ^Label.

Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms/laboratory findings suggesting lactic acidosis or hepatotoxicity.

Affected organisms

• Human Immunodeficiency Virus

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Bictegravir can be increased when it is combined with Abametapir.
Abemaciclib	The excretion of Abemaciclib can be decreased when combined with Bictegravir.
Acyclovir	The excretion of Acyclovir can be decreased when combined with Bictegravir.
Adenine	The metabolism of Bictegravir can be decreased when combined with Adenine.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Bictegravir.
Amitriptyline	The metabolism of Bictegravir can be decreased when combined with Amitriptyline.
Anthrax vaccine	The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Bictegravir.
Atazanavir	The metabolism of Bictegravir can be decreased when combined with Atazanavir.
Bacillus calmette-guerin substrain connaught live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Bictegravir.
Bacillus calmette-guerin substrain tice live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Bictegravir.

Additional Data Available

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Evidence Level
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Food Interactions

• Avoid St. John's Wort.
• Take at the same time every day.
• Take separate from antacids. Take bictegravir at least 2 hours before or 6 hours after taking antacids containing aluminum or magnesium.
• Take with food. When taking iron or calcium-containing products, bictegravir should be taken with food.
• Take with or without food.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Bictegravir sodium	4L5MP1Y7W7	1807988-02-8	WJNFBIVCQMPPJC-FQYDJHLKSA-M

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Biktarvy	Bictegravir sodium (50 mg/1) + Emtricitabine (200 mg/1) + Tenofovir alafenamide fumarate (25 mg/1)	Tablet	Oral	Gilead Sciences, Inc.	2018-02-07	Not applicable
Biktarvy	Bictegravir (50 mg) + Emtricitabine (200 mg) + Tenofovir alafenamide (25 mg)	Tablet	Oral	Gilead Sciences	2018-08-08	Not applicable

Categories

ATC Codes

J05AR20 — Emtricitabine, tenofovir alafenamide and bictegravir

• J05AR — Antivirals for treatment of HIV infections, combinations
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Antiinfectives for Systemic Use
• Antiviral Agents
• Antivirals for Systemic Use
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Direct Acting Antivirals
• Heterocyclic Compounds, Fused-Ring
• MATE 1 Inhibitors
• MATE inhibitors
• UGT1A1 Substrates

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 / 1,3-oxazepines / Hydroxypyridines / Fluorobenzenes / 1,3-oxazinanes / Aryl fluorides / Vinylogous amides / Vinylogous acids / Tertiary carboxylic acid amides / Heteroaromatic compounds / Secondary carboxylic acid amides / Lactams / Cyclic ketones / Oxacyclic compounds / Azacyclic compounds / Organic oxides / Organofluorides / Organonitrogen compounds / Hydrocarbon derivatives

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Substituents

1,3-oxazinane / 2-heteroaryl carboxamide / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carboxamide group / Carboxylic acid derivative / Cyclic ketone / Fluorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Hydroxypyridine / Lactam / Meta-oxazepine / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Oxacycle / Oxazinane / Pyridine carboxylic acid or derivatives / Secondary carboxylic acid amide / Tertiary carboxylic acid amide / Vinylogous acid / Vinylogous amide

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

8GB79LOJ07

CAS number

1611493-60-7

InChI Key

SOLUWJRYJLAZCX-LYOVBCGYSA-N

InChI

InChI=1S/C21H18F3N3O5/c22-9-3-14(23)12(15(24)4-9)6-25-20(30)13-7-26-8-16-27(10-1-2-11(5-10)32-16)21(31)17(26)19(29)18(13)28/h3-4,7,10-11,16,29H,1-2,5-6,8H2,(H,25,30)/t10-,11+,16+/m0/s1

IUPAC Name

(1S,11R,13R)-5-hydroxy-3,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-12-oxa-2,9-diazatetracyclo[11.2.1.0^{2,11}.0^{4,9}]hexadeca-4,7-diene-7-carboxamide

SMILES

OC1=C2N(C[[email protected]]3O[[email protected]@H]4CC[[email protected]@H](C4)N3C2=O)C=C(C(=O)NCC2=C(F)C=C(F)C=C2F)C1=O

References

General References

1. Chase SP, Freimanis AK: Abdominal echography. Ohio State Med J. 1971 Oct;67(10):901-6. [PubMed:5118987]
2. Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1–Infected Adults [Link]
3. BICTEGRAVIR [Link]
4. FDA APPROVES BIKTARVY [Link]
5. BICTEGRAVIR SODIUM [Link]

External Links

PubChem Compound

90311989

PubChem Substance

347828148

ChemSpider

44208822

BindingDB

330048

RxNav

1999660

ChEMBL

CHEMBL3989866

PDBe Ligand

KLQ

Wikipedia

Bictegravir

PDB Entries

6puw / 6rwm / 6rwo

FDA label

Download (720 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Human Immunodeficiency Virus Type 1 (HIV-1) Infection	1
4	Completed	Prevention	ART / Human Immunodeficiency Virus (HIV) Infections	1
4	Completed	Treatment	Human Immunodeficiency Virus (HIV) Infections	1
4	Not Yet Recruiting	Treatment	Coronary Artery Disease (CAD) / Human Immunodeficiency Virus (HIV) Infections	1
4	Not Yet Recruiting	Treatment	Human Immunodeficiency Virus (HIV) Infections	2
4	Not Yet Recruiting	Treatment	Human Immunodeficiency Virus (HIV) Infections / Tuberculosis (TB)	1
4	Recruiting	Other	Drug Use / Human Immunodeficiency Virus Type 1 (HIV-1) Infection	1
4	Recruiting	Prevention	HIV Prevention	1
4	Recruiting	Treatment	Acute HIV Infection	1
4	Recruiting	Treatment	Bone Diseases, Metabolic / Buprenorphine Dependence / Chronic Hepatitis C Virus (HCV) Infection / Co-Infection / HCV Coinfection / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS) / Human Immunodeficiency Virus Type 1 (HIV-1) Infection / Methadone Dependence / Opioid Dependence	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral
Tablet, film coated	Oral	50 MG
Tablet, coated	Oral	50 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US6642245	Yes	2003-11-04	2021-05-04
US6703396	Yes	2004-03-09	2021-09-09
US9296769	No	2016-03-29	2032-08-15
US7803788	No	2010-09-28	2022-02-02
US8754065	No	2014-06-17	2032-08-15
US7390791	No	2008-06-24	2022-05-07
US9216996	No	2015-12-22	2033-12-19
US9708342	No	2017-07-18	2035-06-19
US9732092	No	2017-08-15	2033-12-19
US10385067	No	2019-08-20	2035-06-19
US10548846	No	2016-11-08	2036-11-08

Additional Data Available

Filed On
Filed On
Available for Purchase
The date on which a patent was filed with the relevant government.
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Properties

State

Solid

Experimental Properties

Property	Value	Source
boiling point (°C)	682.5±55.0 °C at 760 mmHg	[L1221]

Predicted Properties

Property	Value	Source
Water Solubility	0.0537 mg/mL	ALOGPS
logP	1.28	ALOGPS
logP	1.36	ChemAxon
logS	-3.9	ALOGPS
pKa (Strongest Acidic)	9.81	ChemAxon
pKa (Strongest Basic)	-0.3	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	6	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	99.18 Å2	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	105.44 m3·mol-1	ChemAxon
Polarizability	41.14 Å3	ChemAxon
Number of Rings	5	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

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Drug created on October 20, 2016 14:49 / Updated on June 12, 2020 11:42