INDICATION For the treatment of influenza A and B virus infection [L1473, L1475], [FDA 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 [FDA 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 [FDA label]. The estimated background risk of major birth defects and miscarriage for the indicated population is not known at this time [FDA 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 [FDA label].; ; **Carcinogenicity**; ; Carcinogenicity studies have not been completed with baloxavir marboxil [FDA 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 [FDA 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) [FDA label].

METABOLISM Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity [FDA label].; ;

MOA This drug is a CAP endonuclease inhibitor [L1473]. 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 [A39907].; ; 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 [L1478]. 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 [L1477]. ; ; 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 [L1475].

DESCPRITION Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication. The 50% inhibitory concentration (IC50) of baloxavir was 1.4 to 3.1 nM (n=4) for influenza A viruses and 4.5 to 8.9 nM (n=3) for influenza B viruses in a PA endonuclease assay. Viruses with reduced susceptibility to baloxavir have amino acid substitutions in the PA protein.

DESCRIPTION Baloxavir marboxil is an orally delivered anti-influenza virus drug. It is a prodrug that is converted to baloxavir . Mechanistically baloxavir is a first-in-class inhibitor of the cap-endonuclease (CEN) activity of an acidic protein within the viral polymerase complex that is essential for viral gene transcription and replication. Alternative influenza antivirals (e.g. , peramivir and zanamivir) target the neuraminidase enzyme that is required for fusion and entry of virus into the host cells, and the budding process that releases newly synthesised virions. (GtoPdb)