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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%.
Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.
Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gramnegative bacteria including carbapenemresistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 mL/min, and it is adjusted for patients with < 60 mL/min or ≥ 120 mL/min CrCL. A population pharmacokinetic (PK) model was constructed using 3427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors including infection sites and mechanical ventilation were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was > 90% against MICs ≤ 4 μg/mL for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients including the patients with augmented renal function, ventilation, and/or severe illness.
Liver injury, characterized predominantly by elevated aspartate aminotransferase and alanine aminotransferase, is a common feature of coronavirus disease 2019 (COVID‐19) symptoms caused by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Additionally, SARS‐CoV‐2 infection is associated with acute‐on‐chronic liver failure in patients with cirrhosis and has a notably elevated mortality in patients with alcohol‐related liver disease compared to other etiologies. Direct viral infection of the liver with SARS‐CoV‐2 remains controversial, and alternative pathophysiologic explanations for its hepatic effects are an area of active investigation. In this review, we discuss the effects of SARS‐CoV‐2 and the inflammatory environment it creates on endothelial cells and platelets more generally and then with a hepatic focus. In doing this, we present vascular inflammation and thrombosis as a potential mechanism of liver injury and liver‐related complications in COVID‐19.
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