Safety, Tolerability, and Pharmacokinetics of the Novel Anti-influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings

Abstract

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 treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission

“…However, oral administration of 10 mg/kg BXM in ferrets resulted in rapid drug clearance within the first 24 hours [21] (Fig 1), resulting in the requirement for an alternative administration route. It was found that BXA prepared as a suspension (1 mg/mL) delivered by subcutaneous injection to four locations on the dorsal region as a single treatment (4 mg/kg in total) allowed maintenance of plasma BXA concentrations above the estimated target of effectiveness [19] for >144 hours following treatment (dotted line, Fig 1). This dose and method of BXA administration was therefore used for all subsequent experiments.…”

“…concentrations of BXA (active form) that exceed the estimated target of effectiveness (6.85 ng/ mL) for more than 120 hours, although PK profiles differ between Asian and non-Asian patients (Fig 1) [19,20]. The target plasma BXA concentration of �6.85 ng/mL was set from non-clinical studies in mice as the concentration necessary to exert greater virus reduction than that seen with oseltamivir phosphate.…”

Dynamically Linking Influenza Virus Infection Kinetics, Lung Injury, Inflammation, and Disease Severity

“…to improve therapeutic design. This is particularly important because current antivirals alleviate 12/35 symptoms but do not effectively lower viral loads [91][92][93][94][95][96]. Validated models like the one here have enormous predictive capabilities and should prove useful in forecasting infection dynamics for a variety of scenarios.…”

Evaluation of Drug–Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects

“…Baloxavir marboxil is minimally detected in plasma, while baloxavir acid is mainly detected. Baloxavir acid exhibits linear pharmacokinetics over the dose range tested in a phase I study (6-80 mg) and has a long elimination half-life, 80-100 h after a single oral administration [5]. Baloxavir marboxil and baloxavir acid have the potential to inhibit P-glycoprotein-mediated transport in an in vitro study [4].…”