Kinetic degradation study for the first licensed anti-influenza polymerase inhibitor, baloxavir marboxil, using high-performance liquid chromatography-mass spectrometry.

The first licensed polymerase inhibitor, baloxavir marboxil was recently approved for the treatment of influenza A and B viruses. Furthermore, there is growing interest in testing the antiviral activity of baloxavir marboxil against Coronavirus. Despite its critical clinical value, there is no information on the degradation products, pathways, or kinetics of baloxavir marboxil under various stress conditions. In this study, a new high-performance liquid chromatography-ultraviolet detection method for accurately quantifying baloxavir marboxil in the presence of its degradation products was developed. A study of degradation kinetics revealed that acidic, thermal neutral, and photolytic degradation reactions have zero-order kinetics, whereas basic and oxidative degradation reactions have first-order kinetics. The structural characterization of baloxavir marboxil degradation products was performed by coupling the optimized high-performance liquid chromatography method to the triple-quadrupole tandem mass spectrometer. The proposed approach was validated according to the International Council for Harmonisation Q2 (R1) requirements for accuracy, precision, robustness, specificity, and linearity. The validated new method was successfully used to analyze baloxavir marboxil as raw material and its pharmaceutical dosage form, Xofluza.

Modeling mitigation of influenza epidemics by baloxavir.

Influenza viruses annually kill 290,000-650,000 people worldwide. Antivirals can reduce death tolls. Baloxavir, the recently approved influenza antiviral, inhibits initiation of viral mRNA synthesis, whereas oseltamivir, an older drug, inhibits release of virus progeny. Baloxavir blocks virus replication more rapidly and completely than oseltamivir, reducing the duration of infectiousness. Hence, early baloxavir treatment may indirectly prevent transmission. Here, we estimate impacts of ramping up and accelerating baloxavir treatment on population-level incidence using a new model that links viral load dynamics from clinical trial data to between-host transmission. We estimate that ~22 million infections and >6,000 deaths would have been averted in the 2017-2018 epidemic season by administering baloxavir to 30% of infected cases within 48 h after symptom onset. Treatment within 24 h would almost double the impact. Consequently, scaling up early baloxavir treatment would substantially reduce influenza morbidity and mortality every year. The development of antivirals against the SARS-CoV2 virus that function like baloxavir might similarly curtail transmission and save lives.