Baloxavir marboxil was well-tolerated in a pediatric population and rapidly reduced viral titers, according to research published in Clinical Infectious Diseases. However, the emergence of viruses with amino acid substitutions suggests that alternative dosing regimens should be considered in the youngest patients.

Researchers conducted a prospective, open-label, multicenter study of Japanese pediatric outpatients during the 2016 to 2017 influenza season to assess the safety, pharmacokinetics, clinical, and virologic outcomes of baloxavir therapy.

All participants were between age 1 year and <12 years and had a body weight of ≥5 kg, a diagnosis of influenza, and an ability to swallow tablets. Patients aged ≥7 years were enrolled if they exhibited at least 1 respiratory symptom. All patients received a single, weight-dependent oral dose of baloxavir.

In total, 107 patients received the study drug. Within the intention-to-treat infected population, the median patient age was 8 years; 83.7% of patients had influenza A (H3N2) virus, and 84.6% of patients had a time-to-treatment from onset of influenza of ≤24 hours.

No adverse events or serious adverse events leading to drug discontinuation were reported, although investigators noted 49 adverse events in 37 patients. The most common adverse events was gastrointestinal in nature, including vomiting in 8 patients. Treatment-related adverse events were reported in 4 patients, and all events were grade 1 and resolved spontaneously.

The median time to illness alleviation for patients with influenza A was 44.6 hours (95% CI, 38.9-62.5 hours); 81.6% of patients were alleviated by 120 hours posttreatment. Time to illness alleviation for patients with influenza B was similar to patients with influenza A(H3N2). The median time to fever resolution was 21.4 hours (95% CI, 19.8-25.8 hours). In addition, 11.1% and 10.7% of patients experienced recurrence of fever after day 3 and day 4, respectively, in patients who became afebrile.

In terms of virologic measures, infectious virus titers rapidly declined after day 1 of baloxavir treatment. The median time to sustained cessation of infectious viral detection was 24 hours, with a shorter time for patients with influenza A(H3N2) compared with influenza B (24 vs 144 hours).

Seventy-seven patients in the intention-to-treat infected population had posttreatment baseline samples available for sequencing. No polymerase acidic protein at position I38 (PA/I38T)-substituted viruses were detected pretreatment, but PA/I38T/M-substituted viruses were detected in the last positive sample of 23.4% of patients at days 6 or 9. All patients were infected with influenza A(H3N2). Median time to sustained cessation of viral shedding in patients with PA/I38T/M-substituted viruses was 180 hours compared with 24 hours in patients without the substitution (95% CI, 144-216 and 95% CI, 24-48, respectively), and median time to illness alleviation and fever resolution in patients with PA/I38T/M-substituted viruses was 79.6 hours and 29.5 hours, respectively, vs 42.8 hours and 20.8 hours, respectively, in patients without the substitution.

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A post-hoc analysis identified the differences in age distribution, body weight, and baseline hemagglutinin inhibition antibody between patients with and without PA/I38T/M-substituted viruses. More PA/I38T/M-substituted viruses occurred in patients with a baseline A(H3N2) hemagglutinin inhibition antibody titer <40 than in those with titer ≥40.

“We found that a single, weight-adjusted dose of baloxavir was well tolerated in pediatric influenza patients,” the researchers concluded. “Further study is required to assess whether alternative dose regimens of baloxavir might reduce the frequency of PA/I38X variant virus emergence.”

Disclosure: The research was supported by Shionogi & Co., Ltd. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Hirotsu N, Sakaguchi H, Sato C, et al. Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes [published online September 20, 2019]. Clin Infect Dis. doi: 10.1093/cid/ciz908