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 used to treat influenza. More specifically, it is a first-in-class cap-dependent endonuclease inhibitor that works to block influenza virus proliferation.2,3 It is a prodrug of baloxavir 6 with an improved absorption profile than its active metabolite due to the addition of a phenolic hydroxyl group to its structure.4 Baloxavir marboxil was first globally approved in Japan in February 2018,2 followed by the US approval in October, 2018.5

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 571.55
Monoisotopic: 571.122477593
Chemical Formula
C27H23F2N3O7S
Synonyms
  • Baloxavir marboxil
External IDs
  • S-033188

Pharmacology

Indication

Baloxavir marboxil is an influenza virus polymerase acidic (PA) endonuclease inhibitor indicated for the treatment of acute uncomplicated influenza in patients who have been symptomatic for no more than 48 hours and who are otherwise healthy adults and pediatric patients five years of age and older, or patients 12 years of age and older who are at high-risk of developing influenza-related complications.6

The drug is also indicated for post-exposure prophylaxis of influenza in patients five years of age and older following contact with an individual who has influenza.6

Baloxavir marboxil is associated with a risk for loss of efficacy due to changes in influenza virus such as changes in virus subtypes, emergence of virus resistance, and changes in viral virulence; therefore, the drug should be used after considering available information on drug susceptibility patterns for circulating influenza virus strains.6

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug events
Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events & improve clinical decision support.
Learn more
Pharmacodynamics

Baloxavir marboxil is an antiviral drug that works against influenza virus to block viral replication. It has an 50% inhibitory concentration (IC50) of 1.4 to 3.1 nM for influenza A viruses and 4.5 to 8.9 nM for influenza B viruses in a polymerase acidic (PA) endonuclease assay.6 In murine models of influenza and avian influenza A, baloxavir reduced pulmonary viral loads and increased survival rates of mice.1 The reduction of viral titer was observed within 24 hours of administration, in a dose-dependent manner.2

Mechanism of action

The influenza virus RNA polymerase complex is a heterotrimer made up of three protein subunits - polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA).1 This polymerase complex is an influenza virus-specific enzyme essential for viral gene transcription and replication,6 with its subunits playing different roles in viral mRNA synthesis. The PB2 subunit binds to the cap of host cellular pre-messenger RNA, allowing the PA protein - a cap-dependent endonuclease - to cleave the capped pre-messenger RNA.1,4 This initial step of mRNA synthesis by the PA protein, also known as the "cap-snatching process," provides an RNA primer for the PB1 subunit, which carries out its RNA-dependent RNA polymerase function to proceed with viral mRNA transcription.1

After administration, the prodrug baloxavir marboxil is almost completely hydrolyzed by esterases in the gastrointestinal lumen, intestinal epithelium, liver and blood 3 to its active metabolite, baloxavir.6 Baloxavir selectively inhibits the PA protein,6 blocking the initiation of mRNA synthesis and ultimately influenza virus proliferation.2 Cap-dependent endonuclease is a highly conserved region across influenza strains;4 however, baloxavir is still vulnerable to resistance because amino acid substitutions in the PA protein can lead to reduced viral susceptibility to baloxavir.6

TargetActionsOrganism
APolymerase acidic protein
inhibitor
Influenza A virus (strain A/Puerto Rico/8/1934 H1N1)
Absorption

Following oral administration of 40 mg baloxavir marboxil in adolescents and adults aged 12 years and older, the AUC was 5520 ng x hr/mL and the Cmax was 68.9 ng/mL. Following a 80 mg dose, the the AUC was 6930 ng x hr/mL and the Cmax was 82.5 ng/mL. The Tmax is about four hours. Food decreased Cmax by 48% and AUC0-inf by 36%.6

In pediatric patients aged five to 12 years of age weighing less than 20 kg, the AUCinf was 5830 ng x hr/mL and the Cmax was 148 ng/mL following a 2 mg/kg dose. The AUCinf was 4360 ng x hr/mL and the Cmax was 81.1 ng/mL following a 40 mg dose in pediatric patients who weigh greater than or equal to 20 kg. The Tmax ranged from 3.5 to 4.5 hours.6

Volume of distribution

The volume of distribution is 1180 L.6

Protein binding

Baloxavir, the active metabolite, is 92.9–93.9% bound to human serum proteins. The ratio of blood cell to blood is 48.5–54.4%.6

Metabolism

Baloxavir predominantly undergoes UGT1A3-mediated metabolism to form glucuronic acid conjugate. It is subsequently metabolized by CYP3A4 to form sulfoxide.2,6

Hover over products below to view reaction partners

Route of elimination

Baloxavir is primarily eliminated by biliary excretion. About 80.1% of the total dose is excreted in feces. About 14.7% of the dose is excreted in urine, where 3.3% of the recovered dose is the unchanged parent drug.6

Half-life

The apparent terminal elimination half-life of baloxavir is 79.1 hours.6

Clearance

Clearance of baloxavir is 10.3 L/h.6

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.
Learn more
Improve decision support & research outcomes with our structured adverse effects data.
Learn more
Toxicity

Oral LD50 is >2000 mg/kg in rats.7

There is limited clinical experience with baloxavir overdose. In one ascending single-dose study involving healthy volunteers, up to 80 mg dose of baloxavir was administered without notable safety concerns.1 Treatment of an overdose of baloxavir marboxil should consist of general supportive measures, including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with baloxavir marboxil. Baloxavir, the active ingredient, is unlikely to be significantly removed by dialysis due to high serum protein binding.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
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Baloxavir marboxil.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Baloxavir marboxil.
Bacillus calmette-guerin substrain connaught live antigenThe 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 antigenThe 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 antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Baloxavir marboxil.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Baloxavir marboxil.
Human adenovirus e serotype 4 strain cl-68578 antigenThe therapeutic efficacy of Human adenovirus e serotype 4 strain cl-68578 antigen can be decreased when used in combination with Baloxavir marboxil.
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Baloxavir marboxil.
Typhoid Vaccine LiveThe therapeutic efficacy of Typhoid Vaccine Live can be decreased when used in combination with Baloxavir marboxil.
Varicella zoster vaccine (live/attenuated)The therapeutic efficacy of Varicella zoster vaccine (live/attenuated) can be decreased when used in combination with Baloxavir marboxil.
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more
Food Interactions
  • Avoid antacids. Baloxavir may form a chelate with polyvalent cations in antacids, which may decrease plasma concentrations of baloxavir.
  • Avoid milk and dairy products. Baloxavir may form a chelate with polyvalent cations such as calcium in dairy products, which may decrease plasma concentrations of baloxavir.
  • 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. Food reduces drug absorption, but not to a clinically significant extent.

Products

Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Active Moieties
NameKindUNIICASInChI Key
Baloxavirprodrug4G86Y4JT3F1985605-59-1FIDLLEYNNRGVFR-CTNGQTDRSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
XofluzaTablet80 mgOralHoffmann La RocheNot applicableNot applicableCanada flag
XofluzaTablet, film coated20 mg/1OralA-S Medication Solutions2018-10-24Not applicableUS flag
XofluzaTablet, film coated80 mg/1OralGenentech, Inc.2018-10-24Not applicableUS flag
XofluzaTablet, film coated40 mgOralRoche Registration Gmb H2022-07-25Not applicableEU flag
XofluzaTablet, film coated40 mgOralRoche Registration Gmb H2021-01-28Not applicableEU flag
XofluzaTablet40 mgOralHoffmann La RocheNot applicableNot applicableCanada flag
XofluzaTablet, film coated40 mg/1OralGenentech, Inc.2018-10-24Not applicableUS flag
XofluzaGranule, for solution40 mg/1mLOralGenentech, Inc.2018-10-24Not applicableUS flag
XofluzaTablet, film coated40 mg/1OralA-S Medication Solutions2018-10-24Not applicableUS flag
XofluzaTablet, film coated20 mgOralRoche Registration Gmb H2021-01-28Not applicableEU flag

Categories

ATC Codes
J05AX25 — Baloxavir marboxil
Drug Categories
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
show 12 more
Substituents
1,2,4-triazine / 2-heteroaryl carboxamide / Acetal / Alkylarylthioether / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Aryl thioether / Azacycle / Benzenoid
show 28 more
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. Shirley M: Baloxavir Marboxil: A Review in Acute Uncomplicated Influenza. Drugs. 2020 Jul;80(11):1109-1118. doi: 10.1007/s40265-020-01350-8. [Article]
  4. Abraham GM, Morton JB, Saravolatz LD: Baloxavir: A Novel Antiviral Agent in the Treatment of Influenza. Clin Infect Dis. 2020 Oct 23;71(7):1790-1794. doi: 10.1093/cid/ciaa107. [Article]
  5. FDA NEWS RELEASE: FDA Approves New Drug to Treat Influenza [Link]
  6. FDA Approved Drug Products: XOFLUZA (baloxavir marboxil) tablets or suspension, for oral use (August 2022) [Link]
  7. Genentech: XOFLUZA (Baloxavir Marboxil) MSDS [Link]
KEGG Drug
D11021
ChemSpider
59718643
RxNav
2099995
ChEMBL
CHEMBL4297503
Wikipedia
Baloxavir_marboxil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentFlu caused by Influenza / Viral Respiratory Tract Infection1
3CompletedTreatmentFlu caused by Influenza4
3RecruitingTreatmentFlu caused by Influenza2
2RecruitingTreatmentFlu caused by Influenza / Hematopoietic and Lymphoid Cell Neoplasm1
2, 3RecruitingTreatmentFlu caused by Influenza1
Not AvailableCompletedOtherHealthy Subjects (HS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Granule, for solutionOral40 mg/1mL
Powder1 kg/1kg
TabletOral20 mg
TabletOral40 mg
TabletOral80 mg
Tablet, coatedOral20 mg
Tablet, film coatedOral20 MG
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral40 mg/1
Tablet, film coatedOral40 mg
Tablet, film coatedOral80 mg/1
Tablet, film coatedOral80 mg
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8927710No2015-01-062031-05-05US flag
US9815835No2017-11-142030-06-14US flag
US8987441No2015-03-242031-09-21US flag
US10392406No2019-08-272036-04-27US flag
US10633397No2020-04-282036-04-27US flag
US10759814No2020-09-012037-08-09US flag
US11261198No2018-09-252038-09-25US flag
US11306106No2017-08-092037-08-09US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility0.015 mg/mLhttps://toku-e.com/content/product-documents/1SDS/B079%20Baloxavir%20Marboxil%20A.0%20CLP.pdf
logP2.26https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214410Orig2s000lbl.pdf
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

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein
Organism
Influenza A virus (strain A/Puerto Rico/8/1934 H1N1)
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
This is a 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
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. Shirley M: Baloxavir Marboxil: A Review in Acute Uncomplicated Influenza. Drugs. 2020 Jul;80(11):1109-1118. doi: 10.1007/s40265-020-01350-8. [Article]
  3. FDA Approved Drug Products: XOFLUZA (baloxavir marboxil) tablets or suspension, for oral use (August 2022) [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
In vitro, baloxavir was a weak inhibitor of CYP3A but it is unlikely to cause clinically relevant drug-drug interactions.
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. Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [Article]
  2. FDA Approved Drug Products: XOFLUZA (baloxavir marboxil) tablets or suspension, for oral use (August 2022) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
In vitro, baloxavir was a weak inhibitor of CYP2B6 but it is unlikely to cause clinically relevant drug-drug interactions.
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
In vitro, baloxavir was a weak inhibitor of CYP2C8 but it is unlikely to cause clinically relevant drug-drug interactions.
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Both baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp). In vitro, baloxavir was a weak inhibitor of P-gp but it is unlikely to cause clinically relevant drug-drug interactions.
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. Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [Article]
  2. FDA Approved Drug Products: XOFLUZA (baloxavir marboxil) tablets or suspension, for oral use (August 2022) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
In vitro, baloxavir was a weak inhibitor of BCRP but it is unlikely to cause clinically relevant drug-drug interactions.
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. Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [Article]

Drug created at February 28, 2018 15:53 / Updated at August 23, 2022 20:16