Introduction

Influenza is one of the most common infectious diseases and is highly contagious through airborne transmission. Influenza symptoms can range from mild, such as fatigue, to severe, such as respiratory failure or even death. Infection with influenza can result in loss of workdays, decreased quality of life, and/or mortality. The most effective strategy for treatment of the flu is prevention. The influenza vaccine is recommended in all people 6 months and older. For patients infected with the influenza virus, antiviral medications are an option for treatment. Antivirals commonly seen as treatment options include M2 ion channel inhibitors and neuraminidase inhibitors. However, influenza has become resistant to M2 ion channel inhibitors; therefore, neuraminidase inhibitors have become the mainstay of treatment. Neuraminidase inhibitors include oseltamivir, peramivir, and zanamivir.¹ A novel antiviral recently approved for influenza treatment is baloxavir marboxil. Baloxavir marboxil has a unique mechanism of action compared with M2 ion channel inhibitors and neuraminidase inhibitors. Baloxavir marboxil was FDA approved on October 24, 2018, for the treatment of acute uncomplicated influenza in patients 12 years and older within 48 hours of symptom onset.²

Mechanism of Action

Baloxavir marboxil is a prodrug with the active metabolite of baloxavir. Baloxavir marboxil’s novel mechanism of action is inhibiting polymerase acidic endonuclease. Polymerase acidic endonuclease is an influenza virus–specific enzyme that is required for viral gene transcription. Inhibition of this enzyme inhibits the replication of the influenza virus.^2,3

Microbiology

Influenza A and B susceptibility to baloxavir marboxil and the neuraminidase inhibitors has been tested. Baloxavir marboxil has been found to cover influenza A H1N1, influenza A H3N2, and influenza B as well as influenza strains resistant to neuraminidase inhibitors.⁴ The substitutions of I38T and E199G in the polymerase acidic subunit of endonuclease result in reduced susceptibility to baloxavir marboxil.² One study investigated baloxavir susceptibilities of seasonal influenza during the 2017–2018 flu season in Japan. Influenza A(H1N1)pdm09, influenza A(H3N2), influenza B/Victoria, and influenza B/Yamagata were identified and susceptible to baloxavir marboxil. No viruses were found to contain the polymerase acidic endonuclease I38T substitution.⁴ However, a microbiology study cited in the package insert did identify the emergence of influenza strains with the amino acid substitutions. Cross-resistance is not expected between the neuraminidase inhibitors and baloxavir marboxil because of baloxavir marboxil’s unique mechanism of action.²

Pharmacokinetics

Absorption is decreased when baloxavir marboxil is taken before or with food; however, the drug can still be administered in nonfasted states.³ The Tmax for baloxavir marboxil is 4 hours. No recommendations are in the label to support tablet crushing for tube administration. Baloxavir marboxil is rapidly metabolized to its prodrug, baloxavir. Baloxavir marboxil is primarily metabolized by UGT1A3 and CYP3A4. Baloxavir has a long elimination half-life, 79.1 hours, allowing for one-time dosing and is mainly excreted through the feces.²

Clinical Trials

The phase III trial (CAPSTONE-1) was a double-blind, randomized, placebo-controlled, and oseltamivir controlled trial.⁵ This trial enrolled outpatients 12–64 years old with flu-like symptoms from the United States and Japan. Flu-like symptoms were defined as a fever (defined as temperature of 38°C [100.4°F] or higher), one other systemic symptom (defined as headache, chills, muscle or joint pain, or fatigue), and at least one respiratory symptom (defined as cough, sore throat, or nasal congestion). Participants had to have a symptom duration of less than 48 hours. Patients were excluded if they were pregnant, weighed less than 40 kg, or had illnesses that resulted in hospitalization. Participants were randomized in a 2:2:1 ratio to receive a single oral dose of baloxavir marboxil (40 mg orally for patients weighing less than 80 kg, 80 mg orally for patients weighing 80 kg or more), oseltamivir 75 mg orally twice daily for 5 days, or matching placebos. Patients enrolled who were younger than 19 years were randomly assigned to receive either baloxavir marboxil or placebo. The primary efficacy end point was the time to alleviation of symptoms. The median time to alleviation of symptoms was shorter in the baloxavir marboxil group than in placebo (53.7 hours vs. 80.2 hours, p<0.001). Alleviation of symptoms was faster for participants who started baloxavir marboxil within 24 hours after symptom onset than for placebo (median difference 32.8 hours, p<0.001). Baloxavir marboxil’s time to alleviation of symptoms compared with oseltamivir’s was not statistically significantly different (53.5 hours vs. 53.8 hours, respectively; no p value reported). Baloxavir marboxil had statistically significant differences in viral load reduction compared with placebo by day 1 and compared with oseltamivir by day 2 (p<0.05 for both comparisons). The incidence of reported adverse events was similar between the three treatment arms (20.7% in baloxavir marboxil, 24.6% in placebo, and 24.8% in oseltamivir). The most common adverse events in the baloxavir marboxil arm were diarrhea and bronchitis. Two patients in the baloxavir marboxil group discontinued the drug, one because of bronchitis and pneumonia and one because of bronchitis. No differences in adverse events were reported with respect to the different baloxavir marboxil doses. The CAPSTONE-2 trial, a study of baloxavir marboxil compared with placebo or oseltamivir in patients with influenza at high risk of influenza complications, has not yet been published.⁶

Most Important Risks/Adverse Events

Serious adverse events considered related to baloxavir marboxil were reported in 0.3% of the treatment group. These included ALT/AST increases, abnormal LFTs, and decreased WBCs.⁵ Currently, no pregnancy or lactation data are available.²

Common Adverse Events

Common adverse events with baloxavir marboxil include diarrhea (3.0%), bronchitis (2.6%), nasopharyngitis (1.5%), headache (0.8%), and nausea (1.3%).³

Common Drug Interactions

Polyvalent cations should be separated by 4 hours with baloxavir marboxil. Use of live attenuated intranasal influenza vaccine with baloxavir marboxil has not been studied. When coadministered with itraconazole, no significant changes in the concentration of baloxavir marboxil or its active metabolite were identified. This could indicate that baloxavir marboxil is not affected by CYP3A4 inhibitors such as itraconazole.² Baloxavir marboxil and its active metabolite have not been found to inhibit or induce any CYPs.²

Usual Dosage

Baloxavir marboxil is dosed one time on the basis of body weight. Patients who weigh from 40 kg to less than 80 kg should receive 40 mg orally once. Patients who weigh 80 kg or greater should receive 80 mg orally once. The medication should be taken within the first 48 hours of influenza symptom onset for patients 12 years and older.³

Available Product

Baloxavir marboxil is available as a 20- or 40-mg tablet. The 20-mg tablets come in two different blister packs, one with two 20-mg tablets and one with four 20-mg tablets. The 40-mg tablets also come in two different blister packs, one with one 40-mg tablet and one with two 40-mg tablets.³

Conclusion

Baloxavir marboxil’s place in therapy has not yet been determined. Baloxavir marboxil is available as an oral one-time dose. Currently, baloxavir marboxil may be useful for patients who have a documented allergy to neuraminidase inhibitors. The baloxavir marboxil package insert states to “consider available information on drug susceptibility patterns for circulating influenza virus strains” because baloxavir marboxil has been found to have activity against strains resistant to neuraminidase inhibitors. Influenza resistance testing is not recommended in practice, however. Baloxavir marboxil has not been studied during pregnancy or lactation, in patients younger than 12 years or older than 65, in patients who weigh less than 40 kg, in patients with morbid obesity (BMI greater than 40 kg/m²), in renal impairment (CrCl less than 50 mL/minute), or in severe hepatic impairment (Child-Pugh class C).

References:

1. Centers for Disease Control and Prevention (CDC). Influenza (Flu). Atlanta: CDC, 2018. Available at https://www.cdc.gov/flu/index.htm.

2. Baloxavir marboxil [package insert]. San Francisco: Shionogi & Co., 2018.

3. Koshimichi H, Ishibashi T, Kawaguchi N, et al. Safety, tolerability, and pharmacokinetics of the novel anti-influenza agent baloxavir marboxil in healthy adults: phase I study findings. Clin Drug Investig 2018 Oct 4. [Epub ahead of print]

4. Takashita E, Morita H, Ogawa R, et al. Susceptibility of influenza viruses to the novel cap-dependent endonuclease inhibitor baloxavir marboxil. Front Microbiol 2018;3026:1-7.

5. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 2018;379:913-23.

6. ID Week 2018. Phase 3 Trial of Baloxavir Marboxil in High Risk Influenza Patients (CAPSTONE-2 Study). Available at https://idsa.confex.com/idsa/2018/webprogram/Paper74204.html.