Population Pharmacokinetics of Baloxavir Marboxil in Japanese Pediatric Influenza Patients.

Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight-based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.

Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza.

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.

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

BACKGROUND AND OBJECTIVE: Baloxavir 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). METHODS: Study 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. RESULTS: Baloxavir 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. CONCLUSION: Single-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: First Global Approval.

Baloxavir marboxil (Xofluza™; baloxavir) is an oral cap-dependent endonuclease inhibitor that has been developed by Roche and Shionogi. The drug blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In February 2018, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections. Phase III development is underway in the USA, EU and other countries for this indication. This article summarized the milestones in the development of baloxavir leading to this first global approval for influenza A or B virus infections.

Discovery of a novel class of AKT pleckstrin homology domain inhibitors.

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated K(D) values ranging from 0.8 to 3.0 micromol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro K(D)s for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 micromol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.