Baloxavir marboxil

Identification

Summary

Baloxavir marboxil is a polymerase acidic endonuclease inhibitor used to treat uncomplicated influenza.

Brand Names

Xofluza

Generic Name

Baloxavir marboxil

DrugBank Accession Number

DB13997

Background

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.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Baloxavir marboxil (DB13997)

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Weight

Average: 571.55
Monoisotopic: 571.122477593

Chemical Formula

C₂₇H₂₃F₂N₃O₇S

Synonyms

• Baloxavir marboxil

External IDs

• S-033188

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.

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Associated Conditions

• Flu caused by Influenza
• Acute, uncomplicated Influenza

Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
UPolymerase acidic protein	inhibitor	Influenza A virus (strain A/Puerto Rico/8/1934 H1N1)

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

Adverse Effects

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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.

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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Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Baloxavir marboxil.
Anthrax vaccine	The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Baloxavir marboxil.
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 Baloxavir marboxil.
Bacillus calmette-guerin substrain russian BCG-I live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Baloxavir marboxil.
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 Baloxavir marboxil.
BCG vaccine	The therapeutic efficacy of BCG vaccine can be decreased when used in combination with Baloxavir marboxil.
Deferasirox	The metabolism of Baloxavir marboxil can be decreased when combined with Deferasirox.
Eltrombopag	The metabolism of Baloxavir marboxil can be decreased when combined with Eltrombopag.
Flunitrazepam	The metabolism of Baloxavir marboxil can be decreased when combined with Flunitrazepam.
Gemfibrozil	The metabolism of Baloxavir marboxil can be decreased when combined with Gemfibrozil.

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Food Interactions

• Avoid antacids.
• Avoid multivalent ions. Multivalent ions such as magnesium, calcium, and aluminum can form a chelate with baloxavir, which can reduce the absorption of baloxavir.
• Take with or without food.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Xofluza	Tablet, film coated	40 mg/1	Oral	A-S Medication Solutions	2018-10-24	Not applicable
Xofluza	Tablet	20 mg	Oral	Hoffmann La Roche	Not applicable	Not applicable
Xofluza	Tablet, film coated	20 mg	Oral	Roche Registration Gmb H	2021-01-28	Not applicable
Xofluza	Tablet, film coated	20 mg/1	Oral	Genentech, Inc.	2018-10-24	2022-07-31
Xofluza	Tablet, film coated	80 mg/1	Oral	Genentech, Inc.	2018-10-24	Not applicable
Xofluza	Tablet	80 mg	Oral	Hoffmann La Roche	Not applicable	Not applicable
Xofluza	Tablet, film coated	20 mg/1	Oral	A-S Medication Solutions	2018-10-24	Not applicable
Xofluza	Tablet	40 mg	Oral	Hoffmann La Roche	Not applicable	Not applicable
Xofluza	Tablet, film coated	40 mg	Oral	Roche Registration Gmb H	2021-01-28	Not applicable
Xofluza	Granule, for solution	40 mg/1mL	Oral	Genentech, Inc.	2018-10-24	Not applicable

Categories

ATC Codes

J05AX25 — Baloxavir marboxil

• J05AX — Other antivirals
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Anti-Infective Agents
• 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
• Enzyme Inhibitors
• Heterocyclic Compounds, Fused-Ring
• Oxazines
• Polymerase Acidic Endonuclease Inhibitors
• Pyridines
• Sulfur Compounds
• Thiepins
• UGT1A3 substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as dibenzothiepins. These are compounds containing a dibenzothiepin moiety, which consists of two benzene connected by a thiepine ring.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Benzothiepins

Sub Class

Dibenzothiepins

Direct Parent

Dibenzothiepins

Alternative Parents

2-heteroaryl carboxamides / Alkylarylthioethers / Pyridines and derivatives / Morpholines / Carbonic acid diesters / Benzenoids / Aryl fluorides / 1,2,4-triazines / Vinylogous amides / Tertiary carboxylic acid amides / Heteroaromatic compounds / Lactams / Cyclic ketones / Oxacyclic compounds / Dialkyl ethers / Azacyclic compounds / Acetals / Organopnictogen compounds / Organonitrogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives

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Substituents

1,2,4-triazine / 2-heteroaryl carboxamide / Acetal / Alkylarylthioether / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Aryl thioether / Azacycle / Benzenoid / Carbonic acid derivative / Carbonic acid diester / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Cyclic ketone / Dialkyl ether / Dibenzothiepin / Ether / Heteroaromatic compound / Hydrocarbon derivative / Lactam / Morpholine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Oxazinane / Pyridine / Tertiary carboxylic acid amide / Thioether / Triazine / Vinylogous amide

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans

Chemical Identifiers

UNII

505CXM6OHG

CAS number

1985606-14-1

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

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. [Article]
2. Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [Article]
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. [Article]
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]
11. FDA Approved Drug Products: XOFLUZA (baloxavir marboxil) oral tablets or suspension [Link]

External Links

KEGG Drug

D11021

ChemSpider

59718643

RxNav

2099995

ChEMBL

CHEMBL4297503

Wikipedia

Baloxavir_marboxil

FDA label

Download (594 KB)

MSDS

Download (322 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Flu caused by Influenza / Viral Respiratory Tract Infection	1
4	Not Yet Recruiting	Treatment	Flu caused by Influenza	1
3	Completed	Treatment	Flu caused by Influenza	4
3	Recruiting	Treatment	Flu caused by Influenza	2
2	Not Yet Recruiting	Treatment	Flu caused by Influenza / Hematopoietic and Lymphoid Cell Neoplasm	1
Not Available	Completed	Other	Healthy Subjects (HS)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Granule, for solution	Oral	40 mg/1mL
Powder		1 kg/1kg
Tablet	Oral	20 mg
Tablet	Oral	40 mg
Tablet	Oral	80 mg
Tablet, coated	Oral	20 mg
Tablet, film coated	Oral	20 mg/1
Tablet, film coated	Oral	20 MG
Tablet, film coated	Oral	40 mg
Tablet, film coated	Oral	40 mg/1
Tablet, film coated	Oral	80 mg/1
Tablet, film coated	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8927710	No	2015-01-06	2031-05-05
US9815835	No	2017-11-14	2030-06-14
US8987441	No	2015-03-24	2031-09-21
US10392406	No	2019-08-27	2036-04-27
US10633397	No	2020-04-28	2036-04-27
US10759814	No	2020-09-01	2037-08-09
US11261198	No	2018-09-25	2038-09-25

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Soluble in water	MSDS
logP	2.24	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.0412 mg/mL	ALOGPS
logP	2.12	ALOGPS
logP	3.38	ChemAxon
logS	-4.1	ALOGPS
pKa (Strongest Basic)	-0.6	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	8	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	97.85 Å2	ChemAxon
Rotatable Bond Count	6	ChemAxon
Refractivity	140.76 m3·mol-1	ChemAxon
Polarizability	53.87 Å3	ChemAxon
Number of Rings	6	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Polymerase acidic protein

Kind

Protein

Organism

Influenza A virus (strain A/Puerto Rico/8/1934 H1N1)

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Representative protein from the polymerase acidic proteins group.

General Function

Plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits. The complex transcribes viral mRNAs by using a unique mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. These short capped RNAs are then used as primers for viral mRNAs. The PB2 subunit is responsible for the binding of the 5' cap of cellular pre-mRNAs which are subsequently cleaved after 10-13 nucleotides by the PA subunit that carries the endonuclease activity.

Specific Function

Endonuclease activity

Gene Name

PA

Uniprot ID

P03433

Uniprot Name

Polymerase acidic protein

Molecular Weight

82587.575 Da

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Drug created at February 28, 2018 15:53 / Updated at August 07, 2021 00:11