By Abraham Chang, PharmD

Clinical Pharmacist, Stanford Health Care, Pharmacy Department

Dr. Chang reports no financial relationships relevant to this field of study.

Baloxavir marboxil is a novel, oral, antiviral agent approved by the Food and Drug Administration (FDA) on Oct. 24, 2018, 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. Baloxavir marboxil is converted by hydrolysis to baloxavir, which is a cap-dependent endonuclease inhibitor that results in inhibition of influenza virus replication. Because of the novel mechanism of action, the drug is effective against influenza strains with neuraminidase resistance.1,2,3

In the randomized, double-blind, placebo- and active-controlled, Phase III CAPSTONE-1 trial, investigators compared baloxavir to placebo and oseltamivir in patients 12 years of age and older with influenza A or B. The primary endpoint was time to alleviation of symptoms, which was similar to that of oseltamivir (53.5 hours vs. 53.8 hours) and significantly shorter than placebo (53.7 hours vs. 80.2 hours; P < 0.0001). The median time to cessation of viral shedding was significantly shorter with baloxavir compared to placebo (24 hours vs. 96 hours; P < 0.0001) or oseltamivir (24 hours vs. 72 hours; P < 0.0001).4

In the CAPSTONE-2 study, researchers compared baloxavir to placebo and oseltamivir in influenza patients with at least one higher risk factor defined by the Centers for Disease Control and Prevention (CDC). The primary endpoint was time to improvement of influenza symptoms, which was significantly shorter with baloxavir compared to placebo (73.2 hours vs. 102.3 hours; P < 0.0001), and similar to oseltamivir (81.0 hours; P = 0.8347). In influenza B, the time to improvement of influenza symptoms was significantly shorter with baloxavir compared to oseltamivir (74.6 hours vs. 101.6 hours; P = 0.0251). The median time to cessation of viral shedding was 48 hours, which was significantly shorter than 96 hours for both placebo and oseltamivir patients.5

Resistance

Baloxavir resistance has been observed in the clinical trials. In patients with paired sequenced samples, PA I38T/M amino acid substitutions were found in 9.7% of 370 patients who received baloxavir. No amino acid substitutions were detected in the 95 randomly selected patients who received placebo. Other mutations in PA were detected in approximately 8% of baloxavir and placebo recipients, but their effect has not been assessed. Viral shedding was detected on day 5 in 91% of patients with PA I38T/M virus compared to just 7% in patients without PA substitution.1,2,3

Pharmacokinetics

Baloxavir marboxil is a prodrug that is converted almost completely to its active metabolite, baloxavir, after oral administration. Food decreases the absorption of baloxavir, but there is no specific recommendation from the manufacturer about administration with or without food. Polyvalent cations (calcium, aluminum, magnesium) may form a chelate with baloxavir, so avoiding co-administration with dairy products, antacids, and oral supplements is recommended.1,2 (See Table 1.)

No clinically significant changes in the pharmaco-kinetics of baloxavir and metabolites were observed with CYP3A4 inhibitors, P-gp inhibitors, or UGT inhibitors.1

Table 1. Baloxavir Pharmacokinetics

Absorption

Tmax = 4 hours

Food decreases Cmax 48%, decreases AUC 36%

Distribution

Protein binding 92.9-93.9%

Volume of distribution ~1,180 L

Elimination

Half-life 79.1 hours

Major route of elimination = metabolism

Metabolism

UGT1A3, CYP3A4

Excretion

Excreted in urine 14.7%

Excreted in feces 80.1%

Dosage and Administration

Baloxavir marboxil is given in a single oral dose based on patient weight as noted in Table 2.

Table 2. Baloxavir Dosage

Patient body weight (kg)

Recommended oral dose

40 to 80 kg

40 mg

≥ 80 kg

80 mg

The medication should be administered within 48 hours of the start of influenza symptoms and can be administered with or without food. Co-administration with dairy products, antacids, and oral supplements should be avoided because of possible chelate formation.

No dose adjustments are required in the presence of a creatinine clearance (CrCl) as low as 50 mL/min or in the presence of mild hepatic impairment (Child-Pugh Class B), but the effects of more severe renal or hepatic impairment have not been evaluated.1

Adverse Effects

Baloxavir is well-tolerated in clinical trials. In the Phase III study, adverse events were reported in 20.7% of baloxavir, 24.6% of placebo, and 24.8% of oseltamivir recipients. The most common adverse event was diarrhea (3.0%).

Pregnancy and Lactation

There are no data on administration of baloxavir marboxil in pregnant women. In animal studies, no adverse developmental effects were observed in rats or rabbits with oral administration of baloxavir marboxil at exposure levels approximately five (rats) and seven (rabbits) times the systemic baloxavir exposure at the maximum recommended human dose.1

There are no data on the presence of baloxavir marboxil in lactating females. Baloxavir and its related metabolites were present in the milk of lactating rats.1

Table 3. Average Wholesale Price of Baloxavir and Neuraminidase Inhibitors

Agent

Unit

Average Wholesale Price

Baloxavir

20-mg tablet x 2 therapy pack

40-mg tablet x 2 therapy pack

$180

$180

Peramivir

200 mg vials x 3

$1,140

Zanamivir

5-mg blister powder for inhalation x 20 + Diskhaler inhalation device

$70.80

Oseltamivir

75 mg capsules x 10

30 mg capsules x 10

$154.57

$123.86

Conclusions

Baloxavir has similar efficacy to oseltamivir for time to alleviation of symptoms and superior efficacy to placebo in uncomplicated influenza patients. In high-risk patient populations, baloxavir was found to have a faster time to alleviation of symptoms compared to oseltamivir in influenza B patients. It is well-tolerated, oral, and administered as a one-time dose. Because of its novel mechanism of action, it has activity in influenza strains with neuraminidase resistance. Further studies are ongoing to characterize baloxavir’s efficacy in hospitalized and other high-risk patient populations and as a combination with a neuraminidase inhibitor. Treatment-emergent resistance has been reported and should be considered when using this agent.

REFERENCES

  1. Genentech USA Inc. Baloxavir marboxil (XofluzaTM) 2018. Package insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210854s000lbl.pdf. Accessed March 7, 2019.
  2. Heo YA. Baloxavir: First global approval. Drugs 2018;78:693-697.
  3. Yang T. Baloxavir marboxil: The first cap-dependent endonuclease inhibitor for the treatment of influenza. Ann Pharmacother 2019; Jan. 23. doi: 10.1177/1060028019826565. [Epub ahead of print].
  4. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 2018;379:913-923.
  5. Ison MG, Portsmouth S, Yoshida Y, et al. LB16. Phase 3 trial of baloxavir marboxil in high risk influenza patients (CAPSTONE-2 Study). IDWeek 2018. Abstract presented Oct. 6, 2018. Available at: https://idsa.confex.com/idsa/2018/webprogram/Paper74204.html. Accessed March 6, 2019.