Background and ObjectiveBaloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. This first-in-human phase I study evaluated the safety, tolerability, and pharmacokinetics of baloxavir marboxil/baloxavir acid in healthy Japanese volunteers (Study 1), while food effects were evaluated in a separate phase I, crossover study in healthy Japanese volunteers (Study 2).MethodsStudy 1 participants were randomized to single-dose oral baloxavir marboxil (6, 20, 40, 60, or 80 mg; n = 6 per dose) or placebo (n = 10), while Study 2 participants (n = 15) received single-dose oral baloxavir marboxil 20 mg in fasted, fed, and before-meal states.ResultsBaloxavir marboxil was well tolerated; there were few treatment-emergent adverse events and no serious adverse events/deaths. The mean plasma baloxavir acid concentration 24 h after single-dose (C24) oral baloxavir marboxil 6 mg was 6.92 ng/mL, exceeding the target C24 (6.85 ng/mL) estimated in nonclinical studies. In Study 1, baloxavir acid exposure demonstrated dose-proportional increases in the fasted state, with maximum plasma concentration generally attained within 3.5 h. Terminal elimination half-life ranged from 49 to 91 h. In Study 2, exposure was decreased and apparent clearance increased in the fed and before-meal states versus the fasted state; however, exposure exceeded the target C24 in all states.ConclusionSingle-dose oral baloxavir marboxil was well tolerated, had a favorable safety profile, and had favorable pharmacokinetic characteristics, including a long half-life, supporting single oral dosing. The baloxavir acid area under the plasma concentration-time curve decreased with food intake by approximately 40%.

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 exposureresponse 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.

ABSTRACT:Medication use during lactation is a matter of concern due to unnecessary exposure of infants to drugs. Although some studies have predicted the extent of drug transfer into milk from physicochemical parameters, drug concentration-time profiles in milk have not been predicted or even analyzed yet. In the present study, a drug transfer model was constructed by defining secretion and reuptake clearances (CL sec and CL re , respectively) between milk and plasma based on unbound drug concentrations.

22 23 on July 5, 2020 by guest http://aac.asm.org/ Downloaded from 3 ABSTRACT (250/250 words) 24 Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor, baloxavir acid, 25 reduces the time to improvement of influenza symptoms in patients infected with type A or 26 B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic 27 model for baloxavir acid was developed using 11846 plasma concentration data items from 28 1827 subjects including 2341 plasma concentration data items from 664 patients at high 29 risk of influenza complications. A three-compartment model with first-order elimination 30 and first-order absorption with lag time well described the plasma concentration data. Body 31 weight and race were found to be the most important factors influencing clearance and 32 volume of distribution. The exposures in high-risk patients were similar to those in 33 otherwise healthy patients, and no pharmacokinetic difference was identified regarding any 34 risk factors for influenza complications.35 Exposure-response analyses were performed regarding the time to improvement of 36 symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses 37 suggested that body weight-based dosage, 40 mg for patients weighing < 80 kg and 80 mg 38 for patients weighing ≥ 80 kg, can shorten the time to improvement of influenza symptoms 39 and reduce virus titer for both type A and B influenza virus regardless of the exposure 40 on July 5, 2020 by guest http://aac.asm.org/ Downloaded from 4 levels of the high-risk patients as well as for the otherwise healthy influenza patients. 41 The results of our population pharmacokinetic and exposure-response analyses in patients 42 with risk factors of influenza complications should provide useful information on the 43 pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for 44

The lack of a clinically meaningful drug-drug interaction between baloxavir marboxil and oseltamivir has been established.