Identification

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Name
Baloxavir marboxil
Accession Number
DB13997
Type
Small Molecule
Groups
Approved, Investigational
Description

Baloxavir marboxil is an antiviral drug developed by Shionogi Co., a Japanese pharmaceutical company and Roche for the treatment of influenza A and influenza B infections. The drug was initially approved for use in Japan in February 2018 and approved by the FDA on October 24, 2018 10, 2 for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours Label. Baloxavir marboxil, a cap-endonuclease inhibitor, has a unique mechanism of action when compared to the currently existing neuraminidase inhibitor drug class used to treat influenza infections 1.

Structure
Thumb
Synonyms
  • Baloxavir marboxil
External IDs
S-033188
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
XofluzaTablet, film coated40 mg/1OralA-S Medication Solutions2018-10-24Not applicableUs
XofluzaTablet, film coated40 mg/1OralGenentech, Inc2018-10-24Not applicableUs
XofluzaTablet, film coated20 mg/1OralGenentech, Inc2018-10-24Not applicableUs
XofluzaTablet, film coated20 mg/1OralA-S Medication Solutions2018-10-24Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
505CXM6OHG
CAS number
1985606-14-1
Weight
Average: 571.55
Monoisotopic: 571.122477593
Chemical Formula
C27H23F2N3O7S
InChI Key
RZVPBGBYGMDSBG-GGAORHGYSA-N
InChI
InChI=1S/C27H23F2N3O7S/c1-36-27(35)39-14-38-25-19(33)8-9-31-24(25)26(34)30-10-11-37-12-21(30)32(31)23-15-6-7-18(28)22(29)17(15)13-40-20-5-3-2-4-16(20)23/h2-9,21,23H,10-14H2,1H3/t21-,23+/m1/s1
IUPAC Name
{[(3R)-2-[(2S)-12,13-difluoro-9-thiatricyclo[9.4.0.0^{3,8}]pentadeca-1(15),3,5,7,11,13-hexaen-2-yl]-9,12-dioxo-5-oxa-1,2,8-triazatricyclo[8.4.0.0^{3,8}]tetradeca-10,13-dien-11-yl]oxy}methyl methyl carbonate
SMILES
[H][C@@]12COCCN1C(=O)C1=C(OCOC(=O)OC)C(=O)C=CN1N2[C@H]1C2=CC=C(F)C(F)=C2CSC2=CC=CC=C12

Pharmacology

Indication

For the treatment of influenza A and B virus infection 4,5, Label in patients 12 and older who have been symptomatic for no more than 48 hours. Clinical trials of this drug did not include subjects 65 years of age and older to determine whether they respond in a different way than younger subjects Label.

Associated Conditions
Pharmacodynamics

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease which prevents polymerase function and therefore influenza virus mRNA replication 5, 3. It has shown therapeutic activity against influenza A and B virus infections, including strains resistant to current antiviral agents 1. This drug inhibits an enzyme required for viral replication, thus rapidly treating flu virus infection 5, Label and alleviating the symptoms associated with infection. A single dose of this agent was shown to be superior to placebo in relieving influenza symptoms and superior to both oseltamivir and placebo drug in virologic outcomes (marked by decreased viral load) 1. The safety profile of Baloxavir marboxil compared favorably with that of oseltamivir, making it an effective treatment option for treatment of the flu virus, in one single dose 5, 1.

Mechanism of action

This drug is a CAP endonuclease inhibitor 4. The influenza endonuclease is an essential subdomain of the viral RNA polymerase enzyme. CAP endonuclease processes host pre-mRNAs to serve as primers for viral mRNA and therefore has been a common target for studies of anti-influenza drugs. Inhibiting the activity of endonuclease can block the transcription of mRNA and inactivate the influenza virus 3.

Viral gene transcription is primed by short-capped oligonucleotides that are cleaved from host cell pre mRNA by endonuclease activity. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5' end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription. The N-terminal domain of PA subunit (PAN) has been confirmed to accommodate the endonuclease activity residues, which is highly preserved among subtypes of influenza A virus and is able to fold functionally 7. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5' end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription. The endonuclease domain binds the N-terminal half of PA (PAN) and contains a two-metal (Mn2+) active site that selectively cleaves the pre-mRNA substrate at the 3′ end of a guanine 6.

The administration of a cap-endonuclease inhibitor, such as Baloxavir marboxil, prevents the above process from occurring, exhibiting its action at the beginning of the pathway before CAP endonuclease may exert its action 5.

TargetActionsOrganism
AInfluenza polymerase acidic proteins
inhibitor
Haemophilus influenzae
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

Tmax: 4h Label

Volume of distribution

1180 (V/F, L) Label.

Protein binding

92.9 - 93.9 % Label

Metabolism

Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity Label.

Route of elimination

14.7 % of a single dose is excreted in the urine, and 80.1% excreted in the feces Label

Half life

Terminal elimination half-life: 79.1 h Label.

Clearance

10.3 L/h Label

Toxicity

Ld50 (oral, rats): >2000 mg/kg MSDS

Pregnancy Risk

There are no available data on the use of this drug in pregnant women to predict or inform a drug-associated risk of adverse developmental outcomes. However, there are known risks to the mother and fetus associated with influenza virus infection during pregnancy. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits with oral administration of Baloxavir marboxil at exposures approximately 5 (rats) and 7 (rabbits) times the systemic Baloxavir exposure at the maximum recommended human dose Label. The estimated background risk of major birth defects and miscarriage for the indicated population is not known at this time Label.

Breastfeeding

There are no data on the presence of this drug in human breastmilk, the effects on the breastfed infant, or the effects on milk production. Baloxavir and its related metabolites were present in the milk of lactating rats Label.

Carcinogenicity

Carcinogenicity studies have not been completed with baloxavir marboxil Label.

Mutagenesis

Baloxavir marboxil and the active metabolite, baloxavir, were not shown to be mutagenic in in-vitro and in in-vivo genotoxicity assays, which included bacterial mutation assays in S. typhimurium and E. coli, micronucleus tests with cultured mammalian cells, and in the rodent micronucleus assay Label.

Impairment of Fertility

In a fertility and early embryonic development study in rats, doses of baloxavir marboxil at 20, 200, or 1,000 mg/kg/day were given to female animals for 2 weeks before mating, during mating and until day 7 of pregnancy. Male animals were dosed for 4 weeks before mating and throughout mating. There were no measured effects on fertility, mating performance, or early embryonic development at any dose level, resulting in systemic drug exposure (AUC) approximately 5 times the MRHD (maximum recommended human dose) Label.

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Baloxavir marboxil can be decreased when used in combination with Adenovirus type 7 vaccine live.
Anthrax vaccineThe therapeutic efficacy of Baloxavir marboxil can be decreased when used in combination with Anthrax vaccine.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Baloxavir marboxil can be decreased when used in combination with Bacillus calmette-guerin substrain connaught live antigen.
Bacillus calmette-guerin substrain danish 1331 live antigenThe therapeutic efficacy of Baloxavir marboxil can be decreased when used in combination with Bacillus calmette-guerin substrain danish 1331 live antigen.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Baloxavir marboxil can be decreased when used in combination with Bacillus calmette-guerin substrain tice live antigen.
BCG vaccineThe therapeutic efficacy of Baloxavir marboxil can be decreased when used in combination with BCG vaccine.
DeferasiroxThe metabolism of Baloxavir marboxil can be decreased when combined with Deferasirox.
DovitinibThe metabolism of Baloxavir marboxil can be decreased when combined with Dovitinib.
EltrombopagThe metabolism of Baloxavir marboxil can be decreased when combined with Eltrombopag.
FlunitrazepamThe metabolism of Baloxavir marboxil can be decreased when combined with Flunitrazepam.
Additional Data Available
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  • Severity
    Severity

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  • Evidence Level
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  • Action
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Food Interactions
Not Available

References

General References
  1. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A: Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197. [PubMed:30184455]
  2. Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [PubMed:29623652]
  3. Dong LH, Cao XR: Studies of the Interaction of Influenza Virus RNA Polymerase PAN with Endonuclease Inhibitors. Interdiscip Sci. 2018 Jun;10(2):430-437. doi: 10.1007/s12539-017-0239-2. Epub 2017 Jun 19. [PubMed:28631174]
  4. NME submissions and their additional indications Projects currently in phase II and III [Link]
  5. Cap-dependent Endonuclease Inhibitor S-033188 for the Treatment of Influenza: Results from a Phase 3, Randomized, Double-Blind, Placebo- and Active-Controlled Study in Otherwise Healthy Adolescents and Adults with Seasonal Influenza [Link]
  6. Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor [Link]
  7. A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase [Link]
  8. Pharmacokinetics/pharmacodynamics of S-033188 [Link]
  9. Synergistic Antiviral Activity of S-033188/S-033447, a Novel Inhibitor of Influenza Virus Cap-Dependent Endonuclease, in Combination with Neuraminidase Inhibitors In Vitro [Link]
  10. FDA Approves New Drug to Treat Influenza [Link]
External Links
KEGG Drug
D11021
ChemSpider
59718643
Wikipedia
Baloxavir_marboxil
FDA label
Download (594 KB)
MSDS
Download (322 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentFlu caused by Influenza3
3RecruitingTreatmentFlu caused by Influenza2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral40 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8927710No2015-01-062031-05-05Us
US9815835No2017-11-142030-06-14Us
US8987441No2015-03-242031-09-21Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySoluble in water MSDS
logP2.24MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0412 mg/mLALOGPS
logP2.12ALOGPS
logP3.38ChemAxon
logS-4.1ALOGPS
pKa (Strongest Basic)-0.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area97.85 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity140.76 m3·mol-1ChemAxon
Polarizability53.87 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

1. Influenza polymerase acidic proteins
Kind
Protein group
Organism
Haemophilus influenzae
Pharmacological action
Yes
Actions
Inhibitor
References
  1. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A: Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197. [PubMed:30184455]
  2. A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase [Link]
  3. BALOXAVIR MARBOXIL FDA [File]

Enzymes

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. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. Baloxavir Marboxil FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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
References
  1. Baloxavir Marboxil FDA label [File]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da
References
  1. Baloxavir Marboxil FDA label [File]

Drug created on February 28, 2018 08:53 / Updated on May 01, 2019 11:55