Background: Multidrug-resistant Gram-negative bacterial infections are increasing globally in neonates, infants and children; antibiotic options are limited.
Methods: This international, multicenter, open-label phase 2 study, investigated the pharmacokinetics, safety and tolerability of single-dose and multiple-dose cefiderocol [as a 3-hour infusion (every 8 hours) dosed at 2000 mg for body weight ≥34 kg and at 60 mg/kg for body weight <34 kg], over a range of renal function, in hospitalized pediatric patients with aerobic Gram-negative bacterial infection; multiple-dose patients required standard-of-care systemic antibiotics for 5-14 days. Four cohorts of pediatric patients were enrolled (cohort 1: 12 to <18 years, cohort 2: 6 to <12 years, cohort 3: 2 to <6 years and cohort 4: 3 months to <2 years).
When planning pediatric clinical trials, optimizing the sample size of neonates/infants is essential because it is difficult to enroll these subjects. In this simulation study, we evaluated the sample size of neonates/infants using a model-based optimal approach for identifying their pharmacokinetics for cefiderocol. We assessed the usefulness of data for estimation performance (accuracy and variance of parameter estimation) from adults and the impact of data from very young subjects, including preterm neonates.
View Article and Find Full Text PDFIntroduction: Ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2, shows efficacy and safety in participants with mild to moderate COVID-19. Since urinary recovery of ensitrelvir ranged from 12.9% to 21.
View Article and Find Full Text PDFIntroduction: Patients with thrombocytopenia and chronic liver disease are at increased risk of bleeding during invasive procedures due to low platelet counts. Lusutrombopag, an orally active thrombopoietin receptor agonist, increases platelet count and reduces the need for platelet transfusion in chronic liver disease patients with thrombocytopenia undergoing a planned invasive procedure. The safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease is not known.
View Article and Find Full Text PDFBackground: The need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated with clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable in large part to subtherapeutic antimicrobial exposure and failure to achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol is a novel siderophore cephalosporin with broad in vitro activity against resistant pathogens and is often used to treat critically ill patients, including those receiving CRRT, despite the lack of data to guide dosing in this population.
View Article and Find Full Text PDFCefiderocol is a siderophore cephalosporin for the treatment of infections caused by gram-negative bacteria including carbapenem-resistant strains. The aim of this study was to develop an intrapulmonary pharmacokinetic (PK) model of cefiderocol and assess the PK profile in lungs. An intrapulmonary PK model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 patients with pneumonia requiring mechanical ventilation and 20 healthy subjects.
View Article and Find Full Text PDFJ Pharmacokinet Pharmacodyn
December 2021
In pharmacometrics, understanding a covariate effect on an interested outcome is essential for assessing the importance of the covariate. Variance-based global sensitivity analysis (GSA) can simultaneously quantify contribution of each covariate effect to the variability for the interested outcome considering with random effects. The aim of this study was to apply GSA to pharmacometric models to assess covariate effects.
View Article and Find Full Text PDFConjugation with lipophilic ligands such as cholesterol and α-tocopherol dramatically improves the delivery and efficacy of antisense oligonucleotides (ASOs) in the liver. To estimate the hepatic ASO concentration and the efficacy of ASOs conjugated with lipophilic ligands in mice, we constructed a pharmacokinetic-pharmacodynamic (PK-PD) model that consisted of a two-linear compartment model for the plasma and the hepatic ASO concentration, and two indirect response models for the hepatic apolipoprotein B (Apo-B) mRNA and plasma total cholesterol. The model provided a good fit of the hepatic ASO concentration although it showed an overprediction of Apo-B mRNA and an underprediction of the plasma total cholesterol within 2-fold at a later time after single intravenous administration of ASOs conjugated with lipophilic ligands.
View Article and Find Full Text PDFCefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gram-negative bacteria, including carbapenem-resistant 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 3,427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI).
View Article and Find Full Text PDFThe human mass balance of lusutrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, was characterised in seven healthy male subjects after a single oral dose of [C]-lusutrombopag (2 mg, 100 μCi) in solution. Lusutrombopag was the main component in plasma, accounting for 56% of plasma radioactivity AUC. In plasma, the half-life of radioactivity (70.
View Article and Find Full Text PDFPurpose: Drug-drug interaction (DDI) potentials of lusutrombopag, a thrombopoietin receptor agonist, on the activity of cytochrome P450 (CYP) 3A and of cyclosporine, which inhibits P-glycoprotein and breast cancer resistance protein, on lusutrombopag pharmacokinetics were assessed via clinical studies and physiologically based pharmacokinetic (PBPK) modeling.
Methods: The effect of lusutrombopag on midazolam (a CYP3A probe substrate) pharmacokinetics was assessed in 15 healthy subjects receiving a single midazolam 5-mg dose with or without coadministration of lusutrombopag 0.75 mg for 6 days (first dose: 1.
Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent in vitro activity and in vivo efficacy against most gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In phase 1 studies, cefiderocol demonstrated linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2-3 hours, and a protein binding of 58% in human plasma. Cefiderocol is a time-dependent cephalosporin; the probability of a target attainment at ≥75% of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL is likely to be achieved at the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients.
View Article and Find Full Text PDFPurpose: Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects.
Methods: Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects.
Purpose: Lusutrombopag is a novel, orally active thrombopoietin receptor agonist. This report describes 3 studies aimed at assessing the effects of food and calcium carbonate on the pharmacokinetic parameters of lusutrombopag in healthy subjects.
Methods: Three single-dose, open-label crossover studies were conducted.
Background: Cefiderocol, a novel siderophore cephalosporin, has shown potent activity against Gram-negative bacteria, including MDR pathogens. Cefiderocol is under clinical investigation for the treatment of serious Gram-negative infections including nosocomial pneumonia.
Objectives: This study assessed intrapulmonary penetration after a single intravenous dose of cefiderocol (2000 mg infused over 60 min) in healthy adult males.
Background: Patients with thrombocytopenia associated with chronic liver disease (CLD) are at greater risk of bleeding during invasive procedures. This study characterized the pharmacokinetic/pharmacodynamic (PK/PD) profile of lusutrombopag, a novel thrombopoietin-receptor agonist, using modelling and simulation, and evaluated the appropriate dose regimen for treatment of thrombocytopenia in CLD patients undergoing invasive procedures.
Methods: A population PK/PD model was developed using plasma lusutrombopag concentrations from 78 healthy subjects and 349 CLD patients, as well as platelet counts from 347 of these 349 patients.
The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax, Doribax, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients.
View Article and Find Full Text PDFThe objectives of this study were to characterize the concentration-time profiles of total radioactivity equivalent and unchanged cefiderocol, the route(s) of elimination and mass balance, and safety of cefiderocol after intravenous administration of a single 1000-mg (100 μCi) dose of [ C]-cefiderocol as a 1-hour infusion in healthy adult male subjects. Unchanged cefiderocol accounted for the majority of total radioactivity in plasma, and the partitioning of total radioactivity into red blood cells was negligible. The recovery of total radioactivity was complete in all subjects within 120 hours after initiation of the infusion (101.
View Article and Find Full Text PDFBackground & Aims: Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures.
Methods: We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/μL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan.