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Abstract
Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral
replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its
pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis
of the baloxavir acid was performed using 8310 plasma concentration data points from
1109 subjects. Exposure-response analyses were performed regarding the time to alleviation
of symptoms and the reduction in the influenza virus titer. A 2-compartment model
with first-order absorption and lag time well described the plasma concentration data
for baloxavir acid, and body weight and race were found to be the most important factors
influencing the clearance and distribution volume. A dose regimen based on the body
weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg)
could provide sufficient exposures for expecting efficacy irrespective of body weight
or race; however, the exposures were dependent on the body weight and race. Exposure-response
analyses suggested that the reduction in the influenza virus titer was greater in
any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir
phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic
model and exposure-response relationships would be useful for understanding the pharmacokinetic
and pharmacodynamic characteristics of baloxavir acid.