Baloxavir Marboxil

Uses

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

For the treatment of influenza A and B virus infection , 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 .

Baloxavir Marboxil is also used to associated treatment for these conditions: Acute, uncomplicated Influenza

How Baloxavir Marboxil works

This drug is a CAP endonuclease inhibitor . 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 .

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 . 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 .

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 .

Toxicity

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

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 . The estimated background risk of major birth defects and miscarriage for the indicated population is not known at this time .

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 .

Carcinogenicity

Carcinogenicity studies have not been completed with baloxavir marboxil .

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 .

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) .

Food Interaction

• 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.

Volume of Distribution

1180 (V/F, L) .

Elimination Route

Tmax: 4h

Half Life

Terminal elimination half-life: 79.1 h .

Clearance

10.3 L/h

Elimination Route

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

Innovators Monograph

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