Baloxavir marboxil
Identification
- 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
Structure for Baloxavir marboxil (DB13997)
- Synonyms
- Baloxavir marboxil
- External IDs
- S-033188
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Xofluza Tablet, film coated 20 mg/1 Oral Genentech, Inc 2018-10-24 Not applicable US 
Xofluza Tablet, film coated 40 mg/1 Oral Genentech, Inc 2018-10-24 Not applicable US - International/Other Brands
- Xofluza (Shionogi)
- 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].
Target Actions Organism AInfluenza polymerase acidic proteins inhibitorHaemophilus influenzae - 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
Drug Interaction Aluminum cation The serum concentration of Baloxavir marboxil can be decreased when it is combined with Aluminum cation. Calcium Carbonate The serum concentration of Baloxavir marboxil can be decreased when it is combined with Calcium Carbonate. Calcium cation The serum concentration of Baloxavir marboxil can be decreased when it is combined with Calcium cation. Calcium Citrate The serum concentration of Baloxavir marboxil can be decreased when it is combined with Calcium Citrate. Deferasirox The metabolism of Baloxavir marboxil can be decreased when combined with Deferasirox. Dovitinib The metabolism of Baloxavir marboxil can be decreased when combined with Dovitinib. Eltrombopag The metabolism of Baloxavir marboxil can be decreased when combined with Eltrombopag. Ferric cation The serum concentration of Baloxavir marboxil can be decreased when it is combined with Ferric cation. Ferrous ascorbate The serum concentration of Baloxavir marboxil can be decreased when it is combined with Ferrous ascorbate. Ferrous gluconate The serum concentration of Baloxavir marboxil can be decreased when it is combined with Ferrous gluconate. - Food Interactions
- Not Available
References
- General References
- 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]
- Heo YA: Baloxavir: First Global Approval. Drugs. 2018 Apr;78(6):693-697. doi: 10.1007/s40265-018-0899-1. [PubMed:29623652]
- 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]
- NME submissions and their additional indications Projects currently in phase II and III [Link]
- 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]
- Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor [Link]
- A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase [Link]
- Pharmacokinetics/pharmacodynamics of S-033188 [Link]
- 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]
- 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
Phase Status Purpose Conditions Count 3 Completed Treatment Flu caused by Influenza 2 3 Recruiting Treatment Flu caused by Influenza 3
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Tablet, film coated Oral 20 mg/1 Tablet, film coated Oral 40 mg/1 - Prices
- Not Available
- Patents
- Not Available
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
Taxonomy
- Classification
- Not classified
Targets
References
- 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]
- A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase [Link]
- 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
- 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
- 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
- Baloxavir Marboxil FDA label [File]
Drug created on February 28, 2018 08:53 / Updated on December 16, 2018 07:01