Identification

Name
Bictegravir
Accession Number
DB11799
Type
Small Molecule
Groups
Approved, Investigational
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.

Structure
Thumb
Synonyms
Not Available
External IDs
GS-9883 / GS-9883-01
Product Ingredients
IngredientUNIICASInChI Key
Bictegravir sodium4L5MP1Y7W71807988-02-8WJNFBIVCQMPPJC-FQYDJHLKSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
BiktarvyBictegravir sodium (50 mg/1) + Emtricitabine (200 mg/1) + Tenofovir alafenamide fumarate (25 mg/1)TabletOralGilead Sciences, Inc.2018-02-07Not applicableUs
Categories
UNII
8GB79LOJ07
CAS number
1611493-60-7
Weight
Average: 449.386
Monoisotopic: 449.119855181
Chemical Formula
C21H18F3N3O5
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[C@H]3O[C@@H]4CC[C@@H](C4)N3C2=O)C=C(C(=O)NCC2=C(F)C=C(F)C=C2F)C1=O

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
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].

TargetActionsOrganism
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]

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].

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]
Clearance

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

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
DrugInteraction
(R)-warfarinThe metabolism of Bictegravir can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Bictegravir.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Bictegravir.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Bictegravir.
5-androstenedioneThe metabolism of Bictegravir can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Bictegravir can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Bictegravir.
AbemaciclibThe excretion of Abemaciclib can be decreased when combined with Bictegravir.
AbirateroneThe metabolism of Bictegravir can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Bictegravir can be decreased when combined with Acalabrutinib.
Food Interactions
Not Available

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
ChEMBL
CHEMBL3989866
Wikipedia
Bictegravir
FDA label
Download (720 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHuman Immunodeficiency Virus (HIV)1
1CompletedTreatmentInfection, Human Immunodeficiency Virus I1
2Active Not RecruitingTreatmentInfection, Human Immunodeficiency Virus I1
2, 3Active Not RecruitingTreatmentInfection, Human Immunodeficiency Virus I1
3Active Not RecruitingTreatmentHIV-1-infection1
3Active Not RecruitingTreatmentInfection, Human Immunodeficiency Virus I3
3Not Yet RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1
3Not Yet RecruitingTreatmentHuman Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)1
3RecruitingTreatmentHIV-1/HBV Co-Infection1
4Not Yet RecruitingPreventionHIV Prevention1
4Not Yet RecruitingTreatmentAcute HIV Infection1
4RecruitingTreatmentHIV-1-infection1
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1
Not AvailableNot Yet RecruitingNot AvailableHIV-1-infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6642245Yes2001-05-042021-05-04Us
US6703396Yes2001-09-092021-09-09Us
US9296769No2012-08-152032-08-15Us
US7803788No2002-02-022022-02-02Us
US8754065No2012-08-152032-08-15Us
US7390791No2002-05-072022-05-07Us
US9216996No2013-12-192033-12-19Us
US9708342No2015-06-192035-06-19Us
US9732092No2013-12-192033-12-19Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)682.5±55.0 °C at 760 mmHg[L1221]
Predicted Properties
PropertyValueSource
Water Solubility0.0537 mg/mLALOGPS
logP1.28ALOGPS
logP1.36ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)9.81ChemAxon
pKa (Strongest Basic)-0.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.18 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity105.44 m3·mol-1ChemAxon
Polarizability41.14 Å3ChemAxon
Number of Rings5ChemAxon
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

Taxonomy

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
show 9 more
Substituents
Pyridine carboxylic acid or derivatives / 2-heteroaryl carboxamide / Meta-oxazepine / Fluorobenzene / Halobenzene / Hydroxypyridine / Aryl fluoride / Aryl halide / Benzenoid / Monocyclic benzene moiety
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Yes
Actions
Antagonist
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72547
Uniprot Name
Reverse transcriptase/RNaseH
Molecular Weight
65223.615 Da
Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Yes
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q7ZJM1
Uniprot Name
Integrase
Molecular Weight
32226.645 Da

Enzymes

Kind
Protein
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
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. Modulate...
Gene Name
POU2F2
Uniprot ID
P09086
Uniprot Name
POU domain, class 2, transcription factor 2
Molecular Weight
51208.51 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. Biktarvy FDA label [File]

Drug created on October 20, 2016 14:49 / Updated on November 02, 2018 09:02